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Objective: Cartilage and meniscus are important structures that maintain the health of the knee joint. Early detection of changes in the internal components of cartilage and meniscus before morphological changes occur is essential to prevent and delay the development of osteoarthritis (OA). This study was designed to determine the changes in the matrix composition of morphologically intact cartilage and meniscus during the acute phase of an anterior cruciate ligament (ACL) rupture, as well as the effect of different states of meniscus (intact or tear) on adjacent cartilage during the acute phase., Methods: This cross-sectional study compared and analyzed 50 patients in the acute phase of ACL rupture who underwent surgical treatment and 66 age-, weight- and height-matched healthy volunteers from May 2022 to May 2023 at our institution. Mean T2 relaxation times and effect sizes in different regions of tibiofemoral articular cartilage and meniscus were compared between the two groups using the Mann-Whitney nonparametric t-test, and correlations between different meniscal states and adjacent cartilage were analyzed., Results: Both in the lateral and medial compartments of the knee, T2 relaxation times were significantly higher in all subregions of cartilage and meniscus in the ACL rupture group (p < 0.05), and the site of injury was predominantly centered in the medial compartment (femur, p = 0.000; tibia, p = 0.000; anterior horn, p = 0.000). In the respective compartments, the posterior horn of the lateral meniscus showed a significant positive correlation with the mid-cartilage of the femoral and tibial (r = 0.566, p = 0.035; r = 0.611, p = 0.02); and the posterior horn of the medial meniscus showed a significant positive correlation with the posterior tibial cartilage (r = 0.668, p = 0.018)., Conclusion: During the acute phase of ACL rupture, the internal composition of the cartilage and meniscus undergoes significant changes, even if the morphology is intact. More importantly, the state of the meniscus significantly affects the internal composition of the adjacent cartilage. This is an early warning sign of OA, which should be closely monitored and carefully managed in clinical practice., (© 2024 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Objective: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee., Methods: Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with whole-body Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically., Results: The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα-expressing Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite the presence of synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity., Conclusion: Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: The field of meniscal root preservation has undergone significant advancement over the past decades; however, the challenge remains to fully understand whether meniscal root repair can ultimately arrest or delay osteoarthritic changes., Objective: To assess longitudinal changes in articular cartilage, subchondral bone, and progression to meniscal extrusion (ME) using high-resolution magnetic resonance imaging (MRI)., Methods: Medial meniscus posterior root tear was surgically induced in 39 New Zealand white rabbits. Animals were randomly assigned into three experimental groups: partial meniscectomy after root tear (PM, n ​= ​13); root tear left in situ (CT, n ​= ​13); and transtibial root repair (RR, n ​= ​13). Contralateral limbs were used as healthy controls. High resolution 4.7 Tesla MRI of the knee joint was performed at baseline, after 2-, and 4-months of post-surgery. Cartilage thickness was calculated in medial and lateral compartments. In addition, the evaluation of ME, subchondral bone edema and healing potential after root repair were assessed too., Results: Progressive cartilage thinning, ME, and subchondral bone edema were evident in all 3 study groups after 4-months of follow-up. The mean cartilage thickness in the PM group was 0.53 ​mm (±0.050), 0.57 ​mm (±0.05) in the CT group, and 0.60 ​mm (±0.08) in the RR group. The PM group exhibited significantly higher cartilage loss when compared to the CT and RR groups (p ​< ​0.001). Moreover, progressive ME and subchondral bone edema were associated with a more severe cartilage loss at the final follow-up., Conclusion: Meniscal root repair did not halt but rather reduced the progression of osteoarthritis (OA). Degenerative changes worsened at a rapid rate in the PM group compared to the RR and CT groups. Early cartilage swelling, persistent subchondral edema, and progressive ME predicted a more severe progression to knee OA in the CT and RR groups., Level of Evidence: II., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether tibiofemoral alignment influences early knee osteoarthritis (OA). We hypothesized that varus overload exacerbates early degenerative osteochondral changes, and that valgus underload diminishes early OA., Method: Normal, over- and underload were induced by altering alignment via high tibial osteotomy in adult sheep (n = 8 each). Simultaneously, OA was induced by partial medial anterior meniscectomy. At 6 weeks postoperatively, OA was examined in five individual subregions of the medial tibial plateau using Kellgren-Lawrence grading, quantification of macroscopic OA, semiquantitative histopathological OA and immunohistochemical type-II collagen, ADAMTS-5, and MMP-13 scoring, biochemical determination of DNA and proteoglycan contents, and micro-computed tomographic evaluation of the subchondral bone., Results: Multivariate analyses revealed that OA cartilaginous changes had a temporal priority over subchondral bone changes. Underload inhibited early cartilage degeneration in a characteristic topographic pattern (P ≥ 0.0983 vs. normal), in particular below the meniscal damage, avoided alterations of the subarticular spongiosa (P ≥ 0.162 vs. normal), and prevented the disturbance of otherwise normal osteochondral correlations. Overload induced early alterations of the subchondral bone plate microstructure towards osteopenia, including significantly decreased percent bone volume and increased bone surface-to-volume ratio (all P ≤ 0.0359 vs. normal)., Conclusion: The data provide high-resolution evidence that tibiofemoral alignment modulates early OA induced by a medial meniscus injury in adult sheep. Since underload inhibits early OA, these data also support the clinical value of strategies to reduce the load in an affected knee compartment to possibly decelerate structural OA progression., Competing Interests: Competing interests H.M. received grants from DFG (German Research Foundation), Deutsche Arthrose-Hilfe, Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie, Sorbonne University Paris, and Fidia farmaceutici S.p.A., speaker fees, and travel fees from Novartis and Fidia farmaceutici S.p.A., is a member of the Scientific Advisory Board of Thuasne and Bone therapeutics and received travel fees and was a member of the Scientific Advisory Board of Kolon TissueGene. All other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aim of this study was to evaluate the role of a novel total meniscal implant in promoting meniscal regeneration and protecting articular cartilage in a rabbit model for 3 and 6 months., Methods: Thirty-six New Zealand rabbits were selected and divided into poly(ɛ-caprolactone) (PG-Pg) scaffold group, meniscectomy group and sham group. In this study, it was investigated whether PG-Pg scaffold can prevent articular cartilage degeneration and promote tissue degeneration, and its mechanical properties at 3 and 6 months after surgery were also explored., Result: The degree of articular cartilage degeneration was significantly lower in the PG-Pg scaffold group than in the meniscectomy group. The number of chondrocytes increased in the PG-Pg scaffold at 3 and 6 months, while a gradual increase in the mechanical properties of the PG-Pg stent was observed from 6 months., Conclusion: The PG-Pg scaffold slows down the degeneration of articular cartilage, promotes tissue regeneration and improves biomechanical properties after meniscectomy. This novel meniscus scaffold holds promise for enhancing surgical strategies and delivering superior long-term results for individuals with severe meniscus tears., Level of Evidence: NA., (© 2024 The Authors. Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Purpose: To assess the long-term chondroprotective effect of lateral meniscal allograft transplantation (MAT) using quantitative magnetic resonance imaging (MRI) T2 mapping., Methods: In patients who underwent isolated lateral MAT, quantitative MRI T2 mapping was conducted preoperatively and postoperatively with at minimum follow-up of 7 years to assess the articular cartilage status. On the sagittal section image bisecting the lateral femoral condyle, the weight-bearing portions of the femoral and tibial articular cartilage were divided into 3 segments each-6 segments in total-based on the meniscal coverage area. The regions-of-interest analyses were performed on the 6 segments to measure the mean T2 value. Then the whole layer was divided into deep and superficial layers for further zonal analysis. The longitudinal change in T2 values was statistically analyzed using paired t-tests. Clinical outcome was evaluated using the Lysholm score., Results: A total of 31 patients were included in the study, with the MRI follow-up period of a minimum of 7 years (mean: 8.9 ± 1.3 years; range: 7.0-11.2 years). The mean T2 value of the whole layer showed significant improvement in all segments of the femoral cartilage and the posterior segment of tibial cartilage. In the zonal analysis, the mean T2 value of the tibial cartilage showed significant improvement in the superficial layer of the mid to posterior portion, while the deep layer remained stable. In contrast, the mean T2 value of the femoral cartilage showed significant improvement in the superficial and deep layers in all segments. The mean Lysholm score significantly improved from 62.6 ± 12.8 to 90.9 ± 10.5 (P < .001)., Conclusions: This study suggests that MAT appears to have a long-term chondroprotective effect on the articular cartilage as judged by quantitative T2 mapping., Level of Evidence: Level Ⅳ, case series., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To conduct a systematic review evaluating potential correlations between preoperative articular cartilage integrity on outcomes and survivorship in patients undergoing meniscal allograft transplantation (MAT)., Methods: A literature search was performed by querying SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials from database inception through May 2023 according to the 2020 PRISMA statement. Inclusion criteria were limited to studies reporting on outcomes and survivorship following MAT based on preoperative cartilage status., Results: Sixteen studies, consisting of 1723 patients (n = 1758 total menisci), were identified in six level III and 10 level IV evidence studies. There was high heterogeneity in cartilage grading scales, reporting of concomitant cartilage procedures, and indications for MAT based on osteoarthritis. Patients with lower limb malalignment were either excluded or corrected with an osteotomy. MAT failure rate was reported in nine studies, with four studies reporting a greater rate of failure in knees with higher degrees of cartilage damage. Eight studies reported on clinical outcomes based on cartilage grade, with two studies reporting significant differences in clinical outcomes based on cartilage grade. Of the five studies reporting management of full-thickness chondral defects with cartilage surgery, three studies reported no significant difference in survivorship based on preoperative cartilage grade, while one study reported lower survivorship and one study reported unclear results. No studies found significant differences in survivorship and outcomes between medial and lateral MAT., Conclusions: Conflicting results and high variability in reporting of concomitant cartilage repair and indications for MAT exist in studies evaluating the efficacy of MAT based on articular cartilage status. The degree of preoperative chondral damage did not have a strong relationship with clinical outcomes following MAT. Higher degrees of cartilage damage were associated with higher MAT failure rates, with possible improvement in survivorship when treated with an appropriate cartilage procedure., Level of Evidence: Level IV., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Tranexamic acid (TXA) has been increasingly used in arthroscopic surgery to prevent hemarthrosis. Despite its effectiveness, safety concerns have been raised regarding its potential cytotoxicity to articular cartilage and meniscus following intra-articular injection., Methods: To evaluate the impact of TXA on cartilage and meniscus, a rat model of knee instability was utilized wherein anterior cruciate ligament (ACL) transection surgery was followed by a single intra-articular injection of TXA at varying concentrations (0, 20, 50, 100, and 150 mg/mL) in saline solution. Cell viability assessment of the cartilage and meniscus (n = 6 per group) was conducted at 24 hours, and gross observation and histological analysis of the medial tibial plateau and medial meniscus were conducted at 2, 4, and 8 weeks (n = 6 per group and time point)., Results: The chondrocyte viability was significantly decreased in the 50, 100, and 150 mg/mL TXA groups compared with the specimens injected with saline solution only (saline group) (p = 0.001, p < 0.001, p < 0.001, respectively), as was meniscal cell viability (p = 0.042, p < 0.001, p < 0.001, respectively). At week 8, the saline and 20 and 50 mg/mL groups showed relatively normal appearances, whereas the 100 and 150 mg/mL groups exhibited increased and varying severity of cartilage and meniscal degeneration. In the 150 mg/mL group, the mean Osteoarthritis Research Society International score was significantly higher than that in the saline and 20 mg/mL groups (p = 0.010 and p = 0.007). Additionally, the mean meniscus score in the 150 mg/mL group was significantly higher than that in the saline, 20 mg/mL, and 50 mg/mL groups (p = 0.020, p = 0.021, p = 0.031, respectively)., Conclusions: Our findings indicate that concentrations of TXA at or above 100 mg/mL can lead to decreased cell viability in both cartilage and meniscus, resulting in significant cartilage degeneration in rats with ACL transection. Furthermore, the use of 150 mg/mL of TXA led to significant meniscal degeneration., Clinical Relevance: It is prudent to avoid using concentrations of TXA at or above 100 mg/mL for intra-articular injection, as such concentrations may result in adverse effects on the cartilage and meniscus., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H786 )., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Background: Total meniscectomy for treating massive meniscal tears may lead to joint instability, cartilage degeneration, and even progressive osteoarthritis. The meniscal substitution strategies for advancing reconstruction of the meniscus deserve further investigation., Hypothesis: A decellularized meniscal scaffold (DMS) modified with collagen affinity stromal cell-derived factor (C-SDF1α) may facilitate meniscal regeneration and protect cartilage from abrasion., Study Design: Controlled laboratory study., Methods: The authors first modified DMS with C-SDF1α to fabricate a new meniscal graft (DMS-CBD [collagen-binding domain]). Second, they performed in vitro studies to evaluate the release dynamics, biocompatibility, and differentiation inducibility (osteogenic, chondrogenic, and tenogenic differentiation) on human bone marrow mesenchymal stem cells. Using in vivo studies, they subjected rabbits that received medial meniscectomy to a transplantation procedure to implement their meniscal graft. At postoperative weeks 6 and 12, the meniscal regeneration outcomes and chondroprotective efficacy of the new meniscal graft were evaluated by macroscopic observation, histology, micromechanics, and immunohistochemistry tests., Results: In in vitro studies, the optimized DMS-CBD graft showed notable biocompatibility, releasing efficiency, and chondrogenic inducibility. In in vivo studies, the implanted DMS-CBD graft after total meniscectomy promoted the migration of cells and extracellular matrix deposition in transplantation and further facilitated meniscal regeneration and protected articular cartilage from degeneration., Conclusion: The new meniscal graft (DMS-CBD) accelerated extracellular matrix deposition and meniscal regeneration and protected articular cartilage from degeneration., Clinical Relevance: The results demonstrate that the DMS-CBD graft can serve as a potential meniscal substitution after meniscectomy., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was supported by the Science and Technology Major Project of Changsha (No. kh2102015) and the National Natural Science Foundation of China (Nos. 82230085 and 82272572). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Purpose: To investigate the surgical outcomes of arthroscopic pull-out repair for medial meniscus root tear (MMRT) combined with the marrow stimulation procedures (MSP) for accompanying high-grade cartilage lesions., Methods: Patients who underwent arthroscopic pull-out repair for MMRT between 2010 and 2019 were retrospectively reviewed. Patients who had at least 3 years of follow-up were included and classified into two groups according to whether MSP (microfracture or microdrilling) were performed on cartilage lesions in the medial tibiofemoral joint (group 1, patients with International Cartilage Repair Society [ICRS] grade 0-3a lesions and did not undergo MSP; group 2, patients with ICRS grade 3b-3d lesions and underwent MSP). Comparative analyses, including non-inferiority trials, were conducted between groups for subjective and objective outcomes. In addition, group 2 was further divided into two subgroups according to cartilage lesion size and compared with group 1 (group S, ≤ 2.0 cm 2 ; group L, > 2.0 cm 2 )., Results: A total of 94 patients were included (group 1, 68 patients; group 2, 26 patients). There were no significant differences in clinical scores at postoperative 3 years and final follow-up between groups 1 and 2, but group 2 failed to satisfy the non-inferiority criteria compared to group 1 overall. In objective outcomes, group 2 did not meet the non-inferiority criteria for the rate of osteoarthritis progression compared to group 1, and it also showed a significantly higher proportion of high-grade osteoarthritis at final follow-up (P = 0.044) and a higher degree of osteoarthritis progression than group 1 (P = 0.03 for pre- to postoperative 3 years, and P = 0.006 for pre- to final follow-up). In additional evaluations comparing the subgroups of group 2 and group 1, group S showed relatively favourable results compared to group L in objective outcomes at final follow-up., Conclusion: Patients who underwent arthroscopic pull-out repair for MMRT combined with MSP for accompanying high-grade cartilage lesions showed suboptimal outcomes compared to those with no or low-grade lesions at mid-term follow-up. High-grade cartilage lesions ≤ 2.0 cm 2 may be candidates for the surgical repair of MMRT if MSP are performed, but those with larger lesions may require alternative treatment strategies., Level of Evidence: III., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: This study aimed to determine whether the repair of a medial meniscus posterior root tear (MMPRT) is effective for MMPRT healing, cartilage regeneration, and clinical outcomes in opening wedge high tibial osteotomy (OWHTO)., Methods: This retrospective study included 80 patients who underwent OWHTO and subsequent second-look arthroscopy. The patients were divided into OWHTO-with-MMPRT-repair (n = 40) and OWHTO alone (n = 40) groups, and the healing rates (complete/partial/failure) were compared. Each group was further divided into over- and under-corrected subgroups to compare healing rates. The International Cartilage Repair Society (ICRS) grade, cartilage defect size, Koshino stage, ICRS cartilage repair assessment score of the medial femoral condyle (MFC), and International Knee Documentation Committee (IKDC) scores between the OWHTO-with-MMPRT-repair and OWHTO alone groups were compared according to whether microfracture was performed on the MFC., Results: The overall healing rate of the MMPRT was higher in the OWHTO-with-MMPRT-repair group than that in the OWHTO alone group (P < 0.001). In addition, in the subgroup analysis, no difference in the MMPRT healing rate between the over-correction and under-correction groups when MMPRT repair was performed (n.s). In contrast, without MMPRT repair, the healing rate was lower in the under-correction group than that in the over-correction group (P = 0.03). Cartilage regeneration of the OWHTO-with-MMPRT-repair group was superior to that of the OWHTO alone group (P < 0.05). The IKDC subjective scores of the OWHTO-with-MMPRT-repair and OWHTO alone groups were 34.5 and 33.1 before surgery (n.s) and 50 and 47.2 at one year after surgery, respectively (n.s). These differences between the two groups for cartilage regeneration and IKDC subjective scores showed the same pattern regardless of microfractures., Conclusions: MMPRT repair during OWHTO might improve MMPRT healing, even with under-correction, and cartilage regeneration of MFC, regardless of microfracture. However, OWHTO with MMPRT repair might not improve short-term clinical outcomes compared to OWHTO alone. Further randomized clinical trials are necessary., Level of Evidence: III, Retrospective cohort study., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Objective: To investigate the correlation between the medial meniscal indentation index (MDI) and medial tibiofemoral articular cartilage damage more than 3 degrees in patients aged 40 to 60 years old with suspected or complicated knee osteoarthritis at non-weight-bearing position, and to determine the predictive threshold., Methods: From June 2016 to June 2020, a total of 308 patients who underwent initial knee arthroscopic exploration for chronic knee pain were collected. The age ranged from 36 to 71 years old with an average of(56.40±1.82) years old, including 105 males and 203 females. And patients with extra-articular malformations (abnormal force lines), a history of trauma, inflammatory arthritis and other specific arthritis were excluded. Finally, 89 eligible cases were obtained, aged from 42 to 60 years old with an average of (59.50±0.71) years old, including 45 males and 44 females. The degree of cartilage damage in the medial compartment of the knee joint was recorded, which was divided into two groups(≥degree 3 and

Objective: Disruption of endogenous glucocorticoid signalling in bone cells attenuates osteoarthritis (OA) in aged mice, however, the role of endogenous glucocorticoids in chondrocytes is unknown. Here, we investigated whether deletion of the glucocorticoid receptor, specifically in chondrocytes, also alters OA progression., Design: Knee OA was induced by surgical destabilisation of the medial meniscus (DMM) in male 22-week-old tamoxifen-inducible glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n = 7-9/group). Mice were harvested 2, 4, 8 and 16 weeks after surgery to examine the spatiotemporal changes in molecular, cellular, and histological characteristics., Results: At all time points following DMM, cartilage damage was significantly attenuated in chGRKO compared to WT mice. Two weeks after DMM, WT mice exhibited increased chondrocyte and synoviocyte hypoxia inducible factor (HIF)-2α expression resulting in extensive synovial activation characterised by synovial thickening and increased interleukin-1 beta expression. At 2 and 4 weeks after DMM, WT mice displayed pronounced chondrocyte senescence and elevated catabolic signalling (reduced Yes-associated protein 1 (YAP1) and increased matrix metalloprotease [MMP]-13 expression). Contrastingly, at 2 weeks after DMM, HIF-2α expression and synovial activation were much less pronounced in chGRKO than in WT mice. Furthermore, chondrocyte YAP1 and MMP-13 expression, as well as chondrocyte senescence were similar in chGRKO-DMM mice and sham-operated controls., Conclusion: Endogenous glucocorticoid signalling in chondrocytes promotes synovial activation, chondrocyte senescence and cartilage degradation by upregulation of catabolic signalling through HIF-2α in murine posttraumatic OA. These findings indicate that inhibition of glucocorticoid signalling early after injury may present a promising way to slow osteoarthritic cartilage degeneration., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To develop a tool allowing to classify the magnitude of structural tissue damage occurring in ACL injured knees. The proposed ACL Injury Severity Scale (ACLISS) would provide an easy description and categorization of the wide spectrum of injuries in patients undergoing primary ACL reconstruction, reaching from isolated ACL tears to ACL injuries with a complex association of combined structural damage., Methods: A stepwise approach was used to develop the ACLISS. The eligibility of each item was based on a literature search and a consensus between the authors after considering the diagnostic modalities and clinical importance of associated injuries to the menisci, subchondral bone, articular cartilage or collateral ligaments. Then, a retrospective analysis of associated injuries was performed in 100 patients who underwent a primary ACL reconstruction (ACLR) by a single surgeon. This was based on acute preoperative MRI (within 8 weeks after injury) as well as intraoperative arthroscopic findings. Depending on their prevalence, the number of selected items was reduced. Finally, an analysis of the overall scale distribution was performed to classify the patients according to different injury profiles., Results: A final scoring system of 12 points was developed (12 = highest severity). Six points were attributed to the medial and lateral tibiofemoral compartment respectively. The amount of associated injuries increased with ACLISS grading. The median scale value was 4.5 (lower quartile 3.0; higher quartile 7.0). Based on these quartiles, a score < 4 was considered to be an injury of mild severity (grade I), a score between ≥ 4 and ≤ 7 was defined as moderately severe (grade II) and a score > 7 displayed the most severe cases of ACL injuries (grade III). The knees were graded ACLISS I in 35%, ACLISS II in 49% and ACLISS III in 16% of patients. Overall, damage to the lateral tibiofemoral compartment was predominant (p < 0.01), but a proportional increase of tissue damage could be observed in the medial tibiofemoral compartment with the severity of ACLISS grading (p < 0.01)., Conclusions: The ACLISS allowed to easily and rapidly identify different injury severity profiles in patients who underwent primary ACLR. Injury severity was associated with an increased involvement of the medial tibiofemoral compartment. The ACLISS is convenient to use in daily clinical practice and represents a feasible grading and documentation tool for a reproducible comparison of clinical data in ACL injured patients., Level of Evidence: Level III., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Anterior cruciate ligament (ACL) injuries in adults are frequently accompanied by meniscal and articular cartilage damage. However, little is known regarding the association, if any, between physical maturity, hypermobility, or bone bruising and these associated injuries in skeletally immature patients with ACL tears., Purpose: To determine if physical maturity, hypermobility, and/or bone bruising is associated with concomitant meniscal and articular cartilage injury in skeletally immature patients with ACL tears., Study Design: Cohort study; Level of evidence, 2., Methods: At 10 institutions in the United States, consecutive skeletally immature patients with complete ACL tears were enrolled between January 2016 and June 2020. Univariable and multivariable logistic regression analysis was used to assess the effect of variables on the likelihood of articular cartilage and meniscal injury., Results: A total of 748 patients were analyzed. Of these, 85 patients (11.4%) had articular cartilage injuries. These patients had a higher bone age (13.9 vs 13.1 years; P = .001), a higher Tanner stage ( P = .009), and increased height (162.9 vs 159.9 cm; P = .03) and were heavier (57.8 vs 54.0 kg; P = .02). For each additional Tanner stage, the odds of articular cartilage injury increased approximately 1.6 times ( P < .001). Of the total patients, 423 (56.6%) had meniscal tears. Those with meniscal tears were older (12.6 vs 12.0 years; P < .001), had a higher bone age (13.5 vs 12.8 years; P < .001), had a higher Tanner stage ( P = .002), had increased height (162.2 vs 157.6 cm; P < .001), and were heavier (56.6 vs 51.6 kg; P < .001). For each additional Tanner stage, the odds of a meniscal tear increased approximately 1.3 times ( P < .001). No association was detected between hypermobility or bone bruising and the likelihood of articular cartilage or meniscal injury. Multivariable regression revealed that increasing Tanner stage was associated with an increasing risk of articular cartilage injury, while weight was associated with an increasing risk of meniscal injury., Conclusion: Increasing physical maturity is associated with increased risks of concomitant articular cartilage and meniscal injury in skeletally immature patients with ACL tears. Hypermobility and bone bruising are not associated with articular cartilage or meniscal injury, suggesting that physical maturity, rather than ligamentous laxity, is the primary risk factor for associated injuries in skeletally immature patients with an ACL tear.

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction., Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient's outcome at 6-year follow-up., Study Design: Cohort study; Level of evidence, 3., Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction., Results: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P ≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation ( P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores ( P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years., Conclusion: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

In this chapter, we describe an induced model of osteoarthritis in mice, frequently employed in the study of this disease. We outline in detail the surgical induction of disease and preparation of samples for histological assessment of disease., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of articular cartilage and thickening and sclerosis of the subchondral bone. Mechanical factors play significant roles in the development and progression of OA, but it is still controversial whether exercise or rest is a more effective treatment for OA patients. In this study, we compared the effects of swimming and immobilization at different stages of OA in mice. Four weeks (the middle stage of OA) or eight weeks (the late stage of OA) after DMM (destabilization of the medial meniscus) surgery, the mice were subjected to four-week immobilization or swimming. Ink blot analysis and a beam walking test were performed to measure the gait and balance ability. Histological analysis was performed to determine the trabecular bone area, the thickness of subchondral bone, the thickness of the cartilage, the OARSI score, and the expression of MMP13 (matrix metalloproteinases) and IL-6 (interleukin). The results showed that at the middle stage of OA, both immobilization and swimming slowed down the progression of OA. Immobilization relieved OA to a certain extent by decreasing the production of regulatory factors to attenuate the degeneration of cartilage, which partly relieved the effects of DMM on gait, mainly in the hindlimb. Swimming mainly attenuated the thickening and rescued the area of subchondral bone., Competing Interests: The authors declare no conflict of interest.

Osteoarthritis (OA) is a common disorder and a major cause of disability in the elderly population. WNT16 has been suggested to play important roles in joint formation, bone homeostasis and OA development, but the mechanism of action is not clear. Transgenic mice lacking Wnt16 expression (Wnt16-/-) have a more severe experimental OA than control mice. In addition, Wnt16-/- mice have a reduced cortical thickness and develop spontaneous fractures. Herein, we have used Cre-Wnt16flox/flox mice in which Wnt16 can be conditionally ablated at any age through tamoxifen-inducible Cre-mediated recombination. Wnt16 deletion was induced in 7-week-old mice to study if the Cre-Wnt16flox/flox mice have a more severe OA phenotype after destabilizing the medial meniscus (DMM surgery) than littermate controls with normal Wnt16 expression (Wnt16flox/flox). WNT16 deletion was confirmed in articular cartilage and cortical bone in Cre-Wnt16flox/flox mice, shown by immunohistochemistry and reduced cortical bone area compared to Wnt16flox/flox mice. After DMM surgery, there was no difference in OA severity in the articular cartilage in the knee joint between the Cre-Wnt16flox/flox and Wnt16flox/flox mice in neither female nor male mice. In addition, there was no difference in osteophyte size in the DMM-operated tibia between the genotypes. In conclusion, inactivation of Wnt16 in adult mice do not result in a more severe OA phenotype after DMM surgery. Thus, presence of WNT16 in adult mice does not have an impact on experimental OA development. Taken together, our results from Cre-Wnt16flox/flox mice and previous results from Wnt16-/- mice suggest that WNT16 is crucial during synovial joint establishment leading to limited joint degradation also later in life, after onset of OA. This may be important when developing new therapeutics for OA treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Törnqvist et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain in knee osteoarthritis (OA)., Design: A search of the Medline, Excerpta Medica database (EMBASE) and Cochrane library databases was performed for original publications reporting association between imaging-detected meniscal pathology (extrusion or tear/damage) and longitudinal and cross-sectional assessments of hyaline articular cartilage loss [assessed on magnetic resonance imaging (MRI)], incident joint replacement and pain (longitudinal and cross-sectional) in knee OA. Each association was qualitatively characterised by a synthesis of data from each analysis, based upon study design and quality scoring (including risk of bias assessment and adequacy of covariate adjustment using Cochrane recommended methodology)., Results: In total 4,878 abstracts were screened and 82 publications were included (comprising 72 longitudinal analyses and 49 cross-sectional). Using high quality, well-adjusted data, meniscal extrusion and meniscal tear/damage were associated with longitudinal progression of cartilage loss, cross-sectional cartilage loss severity and joint replacement, independently of age, sex and body mass index (BMI). Medial and lateral meniscal tears were associated with cartilage loss when they occurred in the body and posterior horns, but not the anterior horns. There was a lack of high quality, well-adjusted meniscal pathology and pain publications and no clear independent association between meniscal extrusion or tear/damage with pain severity, progression in pain or incident frequent knee symptoms., Conclusion: Meniscal features have strong associations with cartilage loss and joint replacement in knee OA, but weak associations with knee pain. Systematic review PROSPERO registration number: CRD 42020210910., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Osteoarthritis is the most prevalent musculoskeletal disease in people over 45, leading to an increasing economic and societal cost. Animal models are used to mimic many aspects of the disease. The present protocol describes the destabilization and cartilage scratch model (DCS) of post-traumatic osteoarthritis. Based on the widely used destabilization of the medial meniscus (DMM) model, DCS introduces three scratches on the cartilage surface. The current article highlights the steps to destabilize the knee by transecting the medial meniscotibial ligament followed by three intentional superficial scratches on the articular cartilage. The possible analysis methods by dynamic weight-bearing, microcomputed tomography, and histology are also demonstrated. While the DCS model is not recommended for studies that focus on the effect of osteoarthritis on the cartilage, it enables the study of osteoarthritis development in a shorter time window, with special focus on (1) osteophyte formation, (2) osteoarthritic and injury pain, and (3) the effect of cartilage damage in the whole joint.

Objective: In light of the role of immune cells in OA pathogenesis, the development of sophisticated animal models closely mimicking the immune dysregulation during the disease development and progression could be instrumental for the preclinical evaluation of novel treatments. Among these models, immunologically humanized mice may represent a relevant system, particularly for testing immune-interacting DMOADs or cell therapies before their transfer to the clinic. Our objective, therefore, was to develop an experimental model of OA by destabilization of the medial meniscus (DMM) in humanized mice., Method: Irradiated 5-week-old NOD/LtSz-scid IL2Rγ null (NSG) mice were humanized by intravenous injection of CD34 + human hematopoietic stem cells. The engraftment efficiency was evaluated by flow cytometry 17 weeks after the humanization procedure. Humanized and non-humanized NSG mice underwent DMM or sham surgery and OA development was assessed 1, 6, and 12 weeks after the surgery., Results: 120 days after the humanization, human T and B lymphocytes, macrophages and NK cells, were present in the blood and spleen of the humanized NSG mice. The DMM surgery induced articular cartilage and meniscal alterations associated with an increase in OA and the meniscal score. Moreover, the surgery triggered an inflammatory response that was sustained at a low grade in the DMM group., Conclusions: Our study shows for the first time the feasibility of inducing OA by DMM in humanized mice. This novel OA model could constitute a useful tool to bridge the gap between the preclinical and clinical evaluation of immune interacting DMOADs and cell-based therapies., (Copyright © 2022 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To observe expression of CD38, a key modulator of nicotinamide dinucleotide (NAD+) metabolism in mice with knee osteoarthritis, and protective effect of CD38 inhibition during the osteoarthritis (OA) development., Method: The destabilization of the medial meniscus (DMM) model was performed in mice to mimic the process of OA. Immunofluorescence of CD38 was performed to evaluate its response during the OA process. Limb bud-derived mesenchymal cells were isolated for micromass culture. 100 nM or 1 μM CD38 inhibitor (78c) treatment for 14 days and CD38 sgRNA infection were then used to explore the effects of chondrogenic differentiation via Alcian blue staining. The expressions of chondrogenic markers were detected using RT-PCR and Western blot. To explore the protective effect of CD38 inhibitor on cartilage degradation during OA in vivo, a CD38 inhibitor was injected into the knee joint after DMM operations. Micro-CT analysis and Safranin O-fast green staining were used to evaluate subchondral bone micro-architecture changes and cartilage degeneration., Results: Compared to the control group, the CD38 expression in superficial cartilage was obviously increased in DMM group (P < 0.05). During the normal chondrogenic differentiation, the extracellular matrix formed and expression of Sox9, Col2, aggrecan increased apparently while CD38 expression decreased, which could be reversed with ablation of CD38 in limb bud-derived mesenchymal cells. Consistent with findings in vitro, CD38 blockage via CD38 inhibitor injection protected against osteosclerosis in medial subchondral bone and cartilage degeneration in DMM-induced experimental mice. Compared to the Sham group, DMM mice showed significantly increased values of BV and BV/TV in subchondral bone (P < 0.05) and Mankin score, which could be rescued by 78c treatment (P < 0.05). Also the CD38 inhibitor contributed to homeostasis of anabolism and catabolism by upregulating Sox9, Col2, aggrecan and downregulating Runx2, Col10 and Mmp13., Conclusion: This study primarily implicates CD38 as an important regulator of chondrogenic differentiation. Inhibition of CD38 demonstrated protection against cartilage degeneration, which suggests that CD38 could be a potential therapeutic target for OA., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Purpose: To assess serial change up to 2 years in medial meniscus extrusion (MME) following medial open-wedge high tibial osteotomy (MOWHTO) and to determine whether postoperative changes in MME correlated with clinical outcomes and arthroscopic articular cartilage status., Methods: This study included 26 patients from December 2016 to March 2018 who underwent MOWHTO for primary medial osteoarthritis with varus malalignment. Second-look arthroscopy with plate removal was performed at postoperative 2 years. MME was consecutively measured using coronal magnetic resonance imaging at preoperative and postoperative 3 months, 6 months, 1.5 years, and 2 years. We also assessed which preoperative parameters could reflect the postoperative changes in MME and evaluated whether postoperative clinical outcomes and arthroscopic articular cartilage improvement would be influenced by the MME changes., Results: Regarding the postoperative serial changes in MME values, significant improvement in MME was noted from postoperative 6 months (P = .003), and thereafter, mean MME was further improved with time until postoperative 2 years (P < .001). Regarding the correlation between preoperative parameters and MME changes, preoperative medial proximal tibial angle (MPTA) showed significant correlations in univariate and multivariate analysis (P = .004 and P = .004, respectively). Meanwhile, changes in MME were not correlated with postoperative clinical outcomes or arthroscopic articular cartilage improvement., Conclusion: After MOWHTO, MME improved with time and was significantly correlated with preoperative MPTA. However, the changes in MME after MOWHTO did not reflect postoperative clinical and arthroscopic articular cartilage improvement., Level of Evidence: IV, case series., (Copyright © 2021 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Purpose: Several factors present at the time of posterior cruciate ligament reconstruction (PCLR) may cause the subsequent progression of articular cartilage lesions. This study aimed to evaluate postsurgical articular cartilage lesions which can be seen on MRI in patients who underwent arthroscopic PCLR with or without concomitant meniscal pathology., Material and Methods: A total of sixty-five patients (mean age 35.8 ± 12.3 years) who underwent arthroscopic PCLR were included in this retrospective study. Patients were divided into two groups: ten patients with concomitant meniscal injuries at the time of PCLR who underwent meniscal surgery and fifty-five patients with intact menisci. The cartilage status of all knees was evaluated by MRI and modified Noyes classification., Results: Cartilage lesions were observed in 18 patients (27.7%) on the last follow-up MRI. The cartilage lesions were more common in the medial (15.4%) and patellofemoral (12.3%) compartments than in the lateral compartment (7.7%). Progression of cartilage lesions was present in 11 patients (16.9%) during follow-up MRI. The majority of cartilage lesions with progression were located in the medial compartment. The meniscal pathology group showed a higher prevalence of articular cartilage lesions on the last follow-up MRI (21.8% versus 60%, p = 0.022). In multivariate Cox regression, concomitant meniscal pathology was significantly associated with progression of articular cartilage lesions (p = 0.044)., Conclusion: PCLR patients with associated meniscal pathology showed worse cartilage condition and more progression of cartilage lesions than isolated PCLR patients. Attention to this risk factor might provide more applicable treatment options for potential osteoarthritis prevention strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Previous findings suggest that silent information regulator 2 ortholog 1 (SIRT1) plays essential roles in chondrocytes and prevents osteoarthritis (OA) development. The purpose of this study was to investigate the effects of intraperitoneal (i.p.) and intra-articular (i.a.) administration of the SIRT1 activator SRT2104, which has been approved for use in humans., Design: OA was induced by destabilizing the medial meniscus in the knee joint of 12-week-old CL57BL/6J mice. The mice were divided into 3 groups, that is, the control group, SRT2104 i.p.-injection group, and SRT2104 i.a.-injection group. Tissues were harvested at 4, 8, 12, and 16 weeks postsurgery. OA progression was evaluated using the Osteoarthritis Research Society International (OARSI) score. The production of OA-related proteins in cartilage and synovium was examined by immunohistochemistry., Results: OARSI scores in the control group were significantly higher at 8 and 12 weeks compared with other 2 groups. Immunohistochemical analysis showed that Sirt1 and type-2 collagen significantly increased, whereas MMP-13, ADAMTS-5, IL-1β, IL-6, cleaved caspase 3, PARP p85, acetylated NF-κB p65, and iNOS decreased significantly in cartilage tissues from the i.p. and i.a, SRT2104 groups. In the synovium, more iNOS-positive M1-like macrophages were observed in the control group than in the i.p. and i.a, SRT2104 groups, whereas more CD206-positive M2-like macrophages were detected in the i.p. and i.a. SRT2104 groups., Conclusions: Both i.p. and i.a. SRT2104 injection reduced OA progression in the mouse OA model, suggesting that SRT2104 can serve as a new treatment for OA.

Background: Articular cartilage and meniscal damage are commonly encountered and often treated at the time of anterior cruciate ligament reconstruction (ACLR). Our understanding of how these injuries and their treatment relate to outcomes of ACLR is still evolving., Hypothesis/purpose: The purpose of this study was to assess whether articular cartilage and meniscal variables are predictive of 10-year outcomes after ACLR. We hypothesized that articular cartilage lesions and meniscal tears and treatment would be predictors of the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level outcomes at 10-year follow-up after ACLR., Study Design: Cohort study (prognosis); Level of evidence, 1., Methods: Between 2002 and 2008, individuals with ACLR were prospectively enrolled and followed longitudinally using the IKDC, KOOS, and Marx activity score completed at entry, 2, 6, and 10 years. A proportional odds logistic regression model was built incorporating variables from patient characteristics, surgical technique, articular cartilage injuries, and meniscal tears and treatment to determine the predictors (risk factors) of IKDC, KOOS, and Marx outcomes at 10 years., Results: A total of 3273 patients were enrolled (56% male; median age, 23 years at time of enrollment). Ten-year follow-up was obtained on 79% (2575/3273) of the cohort. Incidence of concomitant pathology at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 22%; lateral femoral condyle [LFC], 15%; medial tibial plateau [MTP], 4%; lateral tibial plateau [LTP], 11%; patella, 18%; trochlea, 8%) and meniscal pathology (medial, 37%; lateral, 46%). Variables that were predictive of poorer 10-year outcomes included articular cartilage damage in the patellofemoral ( P < .01) and medial ( P < .05) compartments and previous medial meniscal surgery (7% of knees; P < .04). Compared with no meniscal tear, a meniscal injury was not associated with 10-year outcomes. Medial meniscal repair at the time of ACLR was associated with worse 10-year outcomes for 2 of 5 KOOS subscales, while a medial meniscal repair in knees with grade 2 MFC chondrosis was associated with better outcomes on 2 KOOS subscales., Conclusion: Articular cartilage injury in the patellofemoral and medial compartments at the time of ACLR and a history of medial meniscal surgery before ACLR were associated with poorer 10-year ACLR patient-reported outcomes, but meniscal injury present at the time of ACLR was not. There was limited and conflicting association of medial meniscal repair with these outcomes.

Posterior cruciate ligament (PCL) injuries commonly occur in association with participation in sporting or recreational activities or due to a direct trauma. Cartilage and meniscal lesions are prevalent in PCL-injured knees with increasing likelihood and severity based on extent and duration of trauma to the knee. As such, comprehensive diagnostics should be performed to ascertain all related pathology, and patients should be thoroughly educated regarding treatment options, likely sequelae including posttraumatic osteoarthritis, and associated outcomes. Treatments should address the joint as an organ, ensuring stability, alignment, and functional tissue restoration are optimized by the most efficient and effective means possible. Compliance with patient- and procedure-specific postoperative management protocols is critical for optimizing successful outcomes for these complex cases. The objectives of this review article are to highlight the likelihood and importance of osteochondral and meniscal pathology in the PCL-injured knee, and to provide the best current evidence regarding comprehensive evaluation and management for PCL-injured knees with cartilage and/or meniscal comorbidities., Competing Interests: J.P.S. reports grants and personal fees from Arthrex, Inc., grants from DePuy Synthes, other from Journal of Knee Surgery, grants from National Institutes of Health (NIAMS & NICHD), personal fees and other from Thieme, grants from U.S. Department of Defense, other from AO Foundation, other from American Orthopaedic Association, other from AO North America, grants from Coulter Foundation, other from Mid-America Orthopaedic Association, personal fees from Orthopedic Designs North America, personal fees from Smith & Nephew, outside the submitted work. J.L.C. reports grants and personal fees from Arthrex, Inc., personal fees from AthleteIQ, grants from ConforMIS, personal fees from CONMED Linvatec, grants from Coulter Foundation, grants from DePuy Synthes, grants and personal fees from Eli Lilly, other from Journal of Knee Surgery, grants from Merial, other from Midwest Transplant Network, grants, personal fees and other from Musculoskeletal Transplant Foundation, grants from National Institutes of Health (NIAMS and NICHD), grants from Purina, grants from Sites Medical, personal fees and other from Thieme, grants from TissueGen Inc, personal fees from Trupanion, grants from U.S. Department of Defense, grants from Zimmer-Biomet, outside the submitted work., (Thieme. All rights reserved.)

Background: Traditionally defined "meniscal" and "mechanical" symptoms are thought to arise from meniscal tears. Yet meniscal tears and cartilage damage commonly coexist in symptomatic knees. To better characterize the primary driver of these symptoms, we investigated whether the presence of preoperative patient-reported knee symptoms (PRKS), including knee catching/locking, grinding/clicking/popping, and pain with pivoting, are associated with various intra-articular pathological conditions diagnosed at knee arthroscopy., Methods: We collected prospective data from 565 consecutive patients who underwent knee arthroscopy from 2012 to 2019 and had PRKS collected via the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The diagnosis of meniscal pathology and concomitant cartilage damage was confirmed and classified intraoperatively. We used multivariable regression models, adjusting for possible confounders, to examine the association of specific pathological conditions of the knee with the presence of preoperative PRKS., Results: Tricompartmental cartilage damage was strongly associated with significantly worse PRKS, with an increase of 0.33 point (95% confidence interval [CI] = 0.08 to 0.58; p = 0.01) on a 0 to 4-point scale. We did not observe an association between meniscal pathology and preoperative PRKS., Conclusions: Contrary to current dogma, this study demonstrates that traditionally defined "meniscal" and "mechanical" knee symptoms are strongly associated with the burden and severity of underlying cartilage damage rather than with specific meniscal pathology., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/G273)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Osteoarthritis (OA), formerly understood to be a result of passive wear, is now known to be associated with chronic inflammation. Cigarette smoking promotes systemic inflammation and has been implicated in increased joint OA incidence in some studies, though the recent observational data on the association are contradictory. We hypothesize that second-hand smoke (SHS) treatment will increase the incidence of OA in a mouse model that has been subjected to a surgical destabilization of the medial meniscus (DMM). To test this hypothesis, we applied either SHS treatment or room air (RA) to mice for 28 days post-DMM surgery. Histopathology findings indicated that the knees of SHS mice exhibited more severe OA than their control counterparts. Increased expression of matrix metalloprotease-13 (MMP-13), an important extracellular protease known to degrade articular cartilage, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), an intracellular effector of inflammatory pathways, were observed in the SHS group. These findings provide greater understanding and evidence for a detrimental role of cigarette smoke on OA progression and systemic inflammation.

Objective: Transforming growth factor β (TGFβ) signaling plays a complex tissue-specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA., Methods: To identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16-week-old male mice (n = 9-11 per group) and female mice (n = 7-11 per group) with an osteocyte-intrinsic ablation of TGFβ receptor type II (TβRII ocy-/- mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16-week-old male mice, we perturbed joint homeostasis by subjecting 8-week-old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA., Results: In all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRII ocy-/- mice, but not female TβRII ocy-/- mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all P < 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (all P < 0.05). TβRII ocy-/- mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling., Conclusion: Our results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA., (© 2020, American College of Rheumatology.)

Background: This study aimed to verify whether the presence of medial meniscus posterior root tear (MMPRT) affects the clinical and radiographic outcomes of medial open-wedge high tibial osteotomy (MOWHTO) compared to the patients without MMPRT for over a midterm follow-up., Methods: One hundred fifty-six knees were retrospectively enrolled that underwent MOWHTO and second-look arthroscopy concomitantly with a minimum 5 years of follow-up. Seventy-four knees with MMPRT (MMPRT group) were identified. Eighty-two knees with intact MMPR were assigned to another group (MMPRI group). All knees with torn medial meniscus with or without MMPRT had an arthroscopic partial meniscectomy during the MOWHTO. Clinical evaluation included range of motion, American Knee Society scores, and Western Ontario and McMaster Universities Osteoarthritis Index scores. Radiologically, the Kellgren-Lawrence grade was assessed preoperatively and at the latest follow-up. Cartilage status was also compared through the 2-stage arthroscopy according to the International Cartilage Repair Society grading., Results: Average age at operation was 55.8 years (range 42-67), and the average follow-up period was 82.2 months (range 60-148). There were no significant differences in clinical outcomes between the groups. Postoperative changes in Kellgren-Lawrence grade and arthroscopic cartilage status showed no significant differences between the groups. Resected MMPR was remodeled in 41.9% (31/74) of the MMPRT group through the second-look arthroscopy., Conclusion: MMPRT does not affect the clinical and radiologic outcomes of MOWHTO compared to those patients without MMPRT over a mid-term follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To quantitatively evaluate degeneration of articular cartilage using magnetic resonance imaging (MRI) T2 mapping before and after arthroscopic surgery for discoid lateral meniscus (DLM)., Methods: We retrospectively reviewed the medical records of patients who underwent arthroscopic reshaping surgery for symptomatic DLM from September 2013 to October 2017 and who had undergone follow-up for ≥2 years. MRI T2 relaxation examinations had been performed preoperatively and at 3, 6, 12, and 24 months postoperatively. The T2 relaxation times of the whole lateral femoral condyle and the tibial plateau were assessed. In addition, the lateral femoral condyle was divided into 3 subcompartmental areas: anterior, middle, and posterior., Results: In total, 30 knees of 27 patients were included in this study. The patients' mean age at operation was 13.3 years (range 6-23 years), and the mean follow-up period was 31.6 months. Saucerization alone was performed in 3 knees and saucerization with repair in 27 knees. The T2 relaxation time of the whole lateral femoral condyle was significantly increased at 3 and 6 months postoperatively and significantly decreased at 12 and 24 months. The T2 relaxation time of the whole lateral tibial plateau was significantly increased at 3 months postoperatively and significantly decreased at 24 months. The T2 relaxation time of the posterior subcompartment of the lateral femoral condyle was significantly increased at 3 months and significantly decreased at 12 and 24 months., Conclusions: The T2 relaxation time of the lateral femorotibial joint cartilage increased at 3 and 6 months postoperatively and then had decreased at 12 and 24 months. Quantitative MRI allowed us to monitor the substantial changes in the cartilage during the early postoperative period and the recovery at the distant time point after reshaping surgery for DLM., Level of Evidence: Level IV, case series., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Meniscal pathology is one of the most common structural knee issues seen and managed by the orthopaedic surgeon. An ever-evolving armamentarium of management options exists that are geared toward the elimination of symptoms and restoration of normal knee function. A common theme among these management options is to preserve meniscal tissue whenever possible through repair or minimization of meniscal excision, as the literature has shown that the loss of meniscal tissue can significantly alter the distribution of forces and contact stresses on knee articular cartilage, thus predisposing the joint to degenerative osteoarthritis. In the setting of meniscal injuries or insufficiency, various advances in repair techniques, use of meniscal allografts, and use of biologic adjuvants have been reported to help preserve and/or attempt to restore the native kinematic properties of the knee. It is important to explore meniscal function, its associated pathologies, and currently available treatment options that are supported by short-term and long-term clinical data.

Given the prevalence and the scope of the personal and societal burden of osteoarthritis (OA), investigators continue to be deeply interested in understanding the pathogenic basis of disease and developing novel disease modifying OA therapies. Because joint trauma/injury is considered a leading predisposing factor in the development of OA, and since posttraumatic OA is one of the most common forms of OA in general, large animal and rodent models of knee injury that accurately recapitulate the OA disease process have become increasingly widespread over the past decade. To enable study in the context of defined genetic backgrounds, investigative teams have developed standardized protocols for injuring the mouse knee that aim to induce a reproducible degenerative process both in terms of severity and temporal pacing of disease progression. The destabilization of the medial meniscus (DMM) is one of the most commonly employed surgical procedure in rodents that reproducibly models posttraumatic OA and allows for the study of disease progression from initiation to end-stage disease. The description provided here sets the stage for both inexperienced and established investigators to employ the DMM procedure, or other similar surgical destabilization methods, to initiate the development of posttraumatic OA in the mouse. Successful application of this method provides a preclinical platform to study the mechanisms driving the pathogenesis of posttraumatic OA and for testing therapeutic strategies to treat it.

The purpose of this study was to identify factors affecting medial meniscus extrusion and cartilage degeneration in medial meniscus root tears (MMRT) and to determine the optimal cut-off values for the factors that predict disease severity. We retrospectively evaluated 86 consecutive patients diagnosed with an isolated MMRT by magnetic resonance imaging (MRI) examinations and arthroscopic procedures for 2 years. Patient-specific factors such as age, sex, the time between injury and MRI (mTIME), the time between injury and surgery (sTIME), the time between MRI and surgery (dTIME), Kellgren-Lawrence (KL) grades, and the mechanical tibiofemoral axis angle (mTFA) were documented. Regression analyses and receiver operating characteristic (ROC) curve analyses were performed. The mTIME was only positively correlated with meniscal extrusion ( r  = 0.425, p  < 0.001). The patients who had grades 3 and 4 cartilage lesions had only significantly higher KL grades and longer sTIME than the patients who had lower grades of cartilage lesion (6.5 months [interquartile range (IQ): 3.0-12.0) vs. 2.5 months [IQ: 0.9-3.9]; p  < 0.001). The cut-off value of mTIME and sTIME were 2.5 and 6 months. Relapse times greater than 2.5 months and 6 months after a specific event were associated with a 7.8-fold increased risk for meniscus extrusion and an 18.2-fold increased risk for cartilage lesions, respectively. The risk of medial extrusion of the meniscus and the severity of articular cartilage lesions increased with time after an injury. The period of time from 2.5 to 6 months after traumatic event might be a critical window for intervention in the patients with MMRT to perform the repair in the status which the meniscus did not extrude more than 3 mm and the cartilage lesion did not progress more than grade 3. This study is a retrospective and uncontrolled case series and reflects level IV of evidence., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Lysosomes are the major catabolic organelle of the cell and regulate the macromolecular and organelle turnover and programmed cell death. Here, we investigated the lysosome dysfunction in cartilage and its role in chondrocytes apoptosis and the associated mechanism., Design: Lysosomal acidification in Osteoarthritis (OA) and aged cartilage was determined by LysoSensor staining. Lysosomal function in chondrocytes was blocked by siRNA mediated depletion of Lysosomal Associated Membrane Protein 2 (LAMP2) or with lysosome inhibitors. Chondrocyte apoptosis was determined by LDH release, Caspase-3/7 activation, TUNEL and PI uptake assays. Loss of mitochondrial membrane potential (MMP/ΔΨM) and mitochondrial superoxide level was determined by JC-1 and MitoSOX staining, respectively. Colocalization of mitochondria with BCL2 associated X (BAX) and Cytochrome c was determined by immunostaining. Destabilization of medial meniscus (DMM) was performed to induce OA in mice., Results: Lysosomal acidification was found to be significantly decreased in aged mouse and human and mouse OA cartilage which also showed increased chondrocyte apoptosis. Inhibition of lysosomal function resulted in increased oxidative stress, accumulation of dysfunctional mitochondria and apoptosis in chondrocytes in monolayer and in cartilage explant cultures. Depletion of LAMP2 expression or treatment of chondrocytes with lysosomal function inhibitors increased the expression and mitochondrial translocation of BAX leading to Cytochrome c release. Lysosomal dysfunction-induced apoptosis in chondrocytes was not blocked by antioxidants MitoTempo or Diphenyleneiodonium (DPI) but was abrogated by inhibiting BAX., Conclusion: Lysosomal dysfunction induce apoptosis in chondrocytes through BAX-mediated mitochondrial damage and release of Cytochrome c. Our data points to lysosomal function restoration and/or BAX inhibition in chondrocytes as a therapeutic approach for OA., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Object: Autophagy maintains cartilage homeostasis and is compromised during osteoarthritis (OA), contributing to cartilage degeneration. We sought to determine if D-isomer TAT-Beclin-1, a potent inducer of autophagy, could attenuate post-traumatic OA in mice., Methods: 10-week-old mice underwent destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA, or sham surgery (control), and injected intra-articularly with D-isomer TAT-Beclin-1 (0.5-2 mg/kg) or PBS 1 week post-surgery for up to 9 weeks. Mice were sacrificed at 2 or 10 weeks post-surgery. Knee joint sections were evaluated by histopathology for cartilage degeneration and synovitis, and immunostaining for key markers of autophagy (LC3B), cell proliferation (nuclear Ki67), activated fibroblasts (αSMA), and cells of hematopoietic origin (CD45)., Results: All D-isomer TAT-Beclin-1-treated DMM mice had no difference in the degree of cartilage degeneration compared to PBS-injected DMM mice. Surprisingly, all D-isomer TAT-Beclin-1-treated mice exhibited substantial synovial hyperplasia, with increased cellularity and ECM deposition (fibrosis-like phenotype), as compared to PBS-injected mice. Synovial effects of D-isomer TAT-Beclin-1 were dose- and injection frequency-dependent. An increased percentage of cells positive for LC3B and nuclear Ki67 were found in the synovial intima early after injection, which persisted after frequent injections., Conclusions: D-isomer TAT-Beclin-1 did not attenuate cartilage degeneration, but rather induced synovial hyperplasia associated with increased expression of key markers of autophagy and cell proliferation and a fibrosis-like phenotype, independent of markers of fibroblast activation or persistent hematopoietic-origin cell infiltration. These data suggest that, if not tissue-targeted, caution should be taken using autophagy activators due to diverse cellular responses in the joint., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Platelet-rich plasma (PRP) is an emerging therapeutic strategy for treatment of osteoarthritis (OA); however, there is a lack of preclinical and clinical evidence for its efficacy and its mechanism of action is unclear. In the current study, we utilized leukocyte poor-PRP (LP-PRP) and leukocyte rich-PRP (LR-PRP) to mimic clinical point of care formulations and assessed their potential to alter disease progression in a mouse model of post-traumatic OA., Method: Three-month-old wild-type male FVB/N mice received destabilization of the medial meniscus (DMM) surgery to induce OA. To assess the efficacy of LP-PRP and LR-PRP, mice were given intraarticular injections at 2-, 7- and 28-days post-surgery. Mice were then assessed at 5-, 9-, and 13-weeks post-surgery for changes in chronic pain using the hot plate nociceptive assay. At 14-weeks, OA pathogenesis was evaluated using histology and phase-contrast μCT., Results: Treatment with LP-PRP and to a lesser extent LR-PRP preserved cartilage volume and surface area compared to phosphate-buffered saline (PBS) as measured by phase-contrast μCT. However, both treatments had higher Osteoarthritis Research Society International (OARSI) and synovitis scores compared to sham, and neither substantially improved scores compared to PBS controls. With respect to thermal hyperalgesia, PBS-treated mice displayed reduced latency to response compared to sham, and LR-PRP but not LP-PRP improved latency to response at 5-, 9- and 13-weeks post-surgery compared to PBS., Conclusion: The results of this study suggest that effects of PRP therapy on OA progression and disease-induced hyperalgesia may be leukocyte-dependent. And while LP-PRP and to a lesser extent LR-PRP protect from volume and surface loss, significant pathology is still seen within OA joints. Future work is needed to understand how the different components of PRP effect OA pathogenesis and pain, and how these could be modified to achieve greater therapeutic efficacy., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D 2 (PGD 2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model., Methods: Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS -/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS -/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group)., Results: Compared to WT mice, L-PGDS -/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS -/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS -/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05)., Conclusion: Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy., (© 2020, American College of Rheumatology.)

Objectives: Subchondral bone may contribute to knee osteoarthritis (OA) pain. Nerve growth factor (NGF) can stimulate nerve growth through TrkA. We aimed to identify how sensory nerve growth at the osteochondral junction in human and rat knees associates with OA pain., Methods: Eleven symptomatic chondropathy cases were selected from people undergoing total knee replacement for OA. Twelve asymptomatic chondropathy cases who had not presented with knee pain were selected post-mortem. OA was induced in rat knees by meniscal transection (MNX) and sham-operated rats were used as controls. Twice-daily oral doses (30 mg/kg) of TrkA inhibitor (AR786) or vehicle were administered from before and up to 28 days after OA induction. Joints were analysed for macroscopic appearances of articular surfaces, OA histopathology and calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerves in medial tibial plateaux, and rats were assessed for pain behaviors., Results: The percentage of osteochondral channels containing CGRP-IR nerves in symptomatic chondropathy was higher than in asymptomatic chondropathy (difference: 2.5% [95% CI: 1.1-3.7]), and in MNX-than in sham-operated rat knees (difference: 7.8% [95%CI: 1.7-15.0]). Osteochondral CGRP-IR innervation was significantly associated with pain behavior in rats. Treatment with AR786 prevented the increase in CGRP-IR nerves in osteochondral channels and reduced pain behavior in MNX-operated rats. Structural OA was not significantly affected by AR786 treatment., Conclusions: CGRP-IR sensory nerves within osteochondral channels are associated with pain in human and rat knee OA. Reduced pathological innervation of the osteochondral junction might contribute to analgesic effects of reduced NGF activity achieved by blocking TrkA., Competing Interests: Conflicts of interest D.A. Walsh: Grants from Arthritis Research UK, while the study was being conducted; grants from Pfizer Ltd, other from Pfizer Ltd, personal fees from GlaxoSmithKline, outside the submitted work. D. F. McWilliams: grants from Pfizer Ltd. The remaining authors have no conflicts of interest to declare., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Due to its abnormal morphology and ultrastructure, discoid lateral meniscus (DLM) is prone to tear and degeneration, leading to clinical symptoms. Arthroscopy is the main treatment for symptomatic DLM; however, postoperative outcomes vary widely due to the effects of diverse factors. This research aims to explore the factors influencing postoperative outcomes of symptomatic DLM., Methods: Patients with DLM who underwent arthroscopic surgery at our hospital from 9/2008 to 9/2015 were enrolled according to the inclusion and exclusion criteria. Fourteen variables, including sex, body mass index (BMI) and other variables, were chosen as factors for study. Knee function was assessed using the International Knee Documentation Committee (IKDC) score. Univariate analyses (Mann-Whitney U test or Kruskall-Wallis rank sum test) and multivariate analyses (ordinal logistic regression) were used to identify the factors that influenced postoperative outcomes. P < 0.05 was considered statistically significant., Results: A total of 502 patients, including 353 females (70.3%) and 149 males (29.7%), were enrolled. The median IKDC score postoperatively (87.4; range, 41.4 ~ 97.7; IQR, 14.6) was higher than that preoperatively (57.6; range, 26.9 ~ 64.9; IQR, 9.7) (P < 0.001). Male sex was predictive of a higher IKDC score (P = 0.023, OR = 1.702). Compared with BMI ≥25 kg/m 2 , < 18.5 kg/m 2 was associated with better IKDC score (P = 0.026, OR = 3.016). Contrasting with age of onset ≥45 years, ≤14 years (P < 0.001, OR = 20.780) and 14 ~ 25 years (P < 0.001, OR = 8.516) were associated with better IKDC score. In comparison with symptoms duration> 24 months, IKDC scores for patients with symptoms duration ≤1 month (P = 0.001, OR = 3.511), 1 ~ 6 months (P < 0.001, OR = 3.463) and 6 ~ 24 months (P < 0.001, OR = 3.254) were significantly elevated. Compared to Outerbridge grade III ~ IV, no injury (P < 0.001, OR = 6.379) and grade I (P = 0.01, OR = 4.332) were associated with higher IKDC score., Conclusions: Arthroscopic treatment of symptomatic DLM is safe and effective, but its clinical efficacy is affected by many factors. Specifically, male sex, BMI < 18.5 kg/m 2 , age of onset < 25 years (especially < 14 years) and symptoms duration < 24 months are conducive to good postoperative outcomes. However, combined articular cartilage injury (Outbridge grade ≥ 2) reduces postoperative effect.

Objective: The etiology of osteoarthritis (OA) is unknown, however, there appears to be a significant contribution from genetics. We have identified recombinant inbred strains of mice derived from LG/J (large) and SM/J (small) strains that vary significantly in their ability to repair articular cartilage and susceptibility to post-traumatic OA due to their genetic composition. Here, we report cartilage repair phenotypes in the same strains of mice in which OA susceptibility was analyzed previously, and determine the genetic correlations between phenotypes., Design: We used 12 recombinant inbred strains, including the parental strains, to test three phenotypes: ear-wound healing (n = 263), knee articular cartilage repair (n = 131), and post-traumatic OA (n = 53) induced by the surgical destabilization of the medial meniscus (DMM). Genetic correlations between various traits were calculated as Pearson's correlation coefficients of strain means., Results: We found a significant positive correlation between ear-wound healing and articular cartilage regeneration (r = 0.71; P = 0.005). We observed a strong inverse correlation between articular cartilage regeneration and susceptibility to OA based on maximum (r = -0.54; P = 0.036) and summed Osteoarthritis Research Society International (OARSI) scores (r = -0.56; P = 0.028). Synovitis was not significantly correlated with articular cartilage regeneration but was significantly positively correlated with maximum (r = 0.63; P = 0.014) and summed (r = 0.70; P = 0.005) OARSI scores. Ectopic calcification was significantly positively correlated with articular cartilage regeneration (r = 0.59; P = 0.021)., Conclusions: Using recombinant inbred strains, our study allows, for the first time, the measurement of genetic correlations of regeneration phenotypes with degeneration phenotypes, characteristic of OA (cartilage degeneration, synovitis). We demonstrate that OA is positively correlated with synovitis and inversely correlated with the ability to repair cartilage. These results suggest an addition to the risk paradigm for OA from a focus on degeneration to regeneration., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine if osteoarthritis (OA) progression and joint tissue-pathology associations link specific animal models to different human OA phenotypes., Design: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logistic-regression., Results: Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r > 0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r > 0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r > 0.4), SCB sclerosis (r > 0.26), osteophyte size (r > 0.3), and maturity (r > 0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r = 0.56), osteophyte maturity (r = 0.49), size (r = 0.45), and SCB sclerosis (r = 0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r = 0.40) and osteophyte size (r = 0.37); and synovitis with cartilage structural damage (r = 0.18). No tissue-pathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR = 2.0) and proteoglycan loss (OR = 2.4) in DMM; and synovitis (OR = 1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR = 1.4) and inversely with osteophyte size (OR = 0.21) in AIA only., Conclusion: This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose: (1) To investigate whether an increased lateral meniscal slope measured on magnetic resonance image (MRI) would be associated with greater risk of bone contusions in noncontact anterior cruciate ligament injury, and (2) to measure the relationship between the occurrence of bone contusions and associated findings observed in ACL deficient knees such as cartilage damage, anterolateral complex injury and concomitant meniscal tears., Method: Patients who underwent ACL reconstruction surgery between 2013 and 2018 were retrospectively reviewed. Sixty-three patients were included in the study group (ACL + bone contusions group), 56 participants were in the control group (isolated ACL group). The presence and severity of bone contusions were determined from preoperative MRIs. The lateral meniscal slope and lateral posterior tibial slope were measured on the MRIs in a blinded fashion. The predictors of lateral bone contusions including age, sex, body mass index, lateral meniscal slope and lateral posterior tibial slope were examined by multivariable logistic regression. Associated findings including concomitant meniscal lesions, intra-articular cartilage damage and anterolateral complex injury, which were also calculated by multivariable logistic regression., Results: The mean lateral meniscal slope in the study group was 6.5° ± 3.5°, which was significantly larger than that in the control group (3.8° ± 2.7°; P < 0.01). In addition, increased lateral meniscal slope was significantly associated with lateral bone contusions in noncontact ACL injury (Lateral femoral condyle (LFC): AOR 16.5; 95% CI 5.40-50.20; P < 0.01; Lateral tibial plateau (LTP): AOR 31.8; 95% CI 8.68-116.7; P < 0.01). However, lateral posterior tibial slope was not significantly associated with bone contusions. Moreover, the presence of lateral bone contusions was associated with concomitant lateral meniscal tears (OR 12.4; 95% CI 3.30-46.30) and cartilage damage (OR 2.9; 95% CI 1.04-8.18)., Conclusion: An increased lateral meniscal slope was associated with increased risk of lateral bone contusions in noncontact ACL injury. In addition, the presence of lateral bone contusions was associated with intra-articular cartilage damage, anterolateral complex injury and concomitant meniscal tears. Hence, additional information was provided for counseling patients who have increased LMS on the greater risk of knee rotational instability and identify patients undergoing ACL reconstruction who may benefit from extra-articular tenodesis., Level of Evidence: IV.

Purpose: To investigate the influences of time from injury to surgery and meniscal injuries on knee rotational laxity in anterior cruciate ligament (ACL)-deficient knees using the electromagnetic system retrospectively., Methods: Ninety-four unilateral ACL-injured patients (44 male and 50 female, mean age: 27.3 ± 11.8 years) were included. The pivot-shift test was performed before ACL reconstruction, as was a quantitative evaluation using the electromagnetic system to determine tibial acceleration. Patients were divided into 4 groups according to the chronicity: group 1, within 3 months (22 patients); group 2, between 3 and 6 months (29 patients); group 3, between 6 and 12 months (23 patients); and group 4, more than 12 months (20 patients). The presence of meniscal injuries was examined arthroscopically., Results: The tibial acceleration was significantly greater in group 4. There was a positive correlation between tibial acceleration and the time from injury to surgery (r = 0.47, P = .02). In groups 1, 2 and 3, the tibial acceleration in patients with a lateral meniscal injury was significantly greater than in patients with a medial meniscal injury and without meniscal injury. When patients with lateral meniscal injury were excluded (leaving those with medial meniscus injury or without meniscal injury), group 4 had significantly greater accelerations than other groups., Conclusions: In ACL-deficient knees, rotational laxity increased with time and the increased rotational laxity was evident more than 1 year after injury whereas it increased with concomitant lateral meniscal injuries within 1 year after injury., Level of Evidence: Ⅳ, diagnostic study of nonconsecutive patients., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Objectives: In this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression., Methods: Destabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by μCT and MRI in non-human primates., Results: Metformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates., Conclusions: The present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)