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Arthrofibrosis of the knee, a complication commonly observed after joint trauma, inflammation, or surgical reconstruction and repair, can lead to significant functional losses in joint range of motion (ROM) and pain. Loss of ROM, even to a small degree, can have significant effects on joint mobility, including limitations in top running speed in athletes and the ability to complete activities of daily living in older populations. Management of arthrofibrosis, including both prevention strategies and treatments, is necessary to maintain functionality of the joint and improve patient outcomes. If a knee does develop symptomatic stiffness that limits motion postoperatively, nonoperative management is indicated for at least 4 to 6 weeks until the inflammation, oedema and pain have decreased. If clinically significant stiffness persists beyond 12 weeks in the postoperative period, arthrofibrosis is usually treated with combined arthroscopic release surgery and then a manipulation under anaesthesia to reduce the risk of fracture or tendon rupture. A systematic approach to restoring range of motion of the knee is recommended during surgical management of arthrofibrosis. Typically, flexion deficits stem from suprapatellar adhesions. Extension deficits, in contrast, often are related to anterior interval scarring and posterior capsular contractures. Equally as critical, aggressive postoperative range of motion therapy coupled with adequate pain control is necessary to maintain range of motion improvements achieved in the operating room.

Preserving capsular integrity has become an important principle of hip preservation surgery given the increasingly recognized deleterious effects of instability in cases of capsular insufficiency. When capsular tissue is deficient, capsular reconstruction may be indicated to restore function of the iliofemoral ligament and improve hip biomechanics. To date, few studies have presented technical guidance on performing arthroscopic capsular reconstruction of the hip. In this Technical Note, we introduce a modified kite technique for arthroscopic entry, control, and fixation of a capsular reconstruction graft. Similar to flying a kite with multiple fly lines, and to the previously described kite technique for hip labral reconstruction, the principles of this method are founded on the belief that control sutures within a pulley system facilitate safe and efficient graft management during capsular reconstruction procedures.

Case A 36-year-old 7'0' male professional basketball player presented with hip pain and radiographic imaging consistent with femoroacetabular impingement syndrome and a labral tear. Hip arthroscopy was performed with the patient positioned supine on a postless distraction table to negate the risk of pudendal nerve and perineal skin complications. Hip distraction was achieved with only 40 lbs (18.14 kg) of distraction force. Labral repair and cam osteochondroplasty were safely performed without complication. Conclusions This case is the first to demonstrate that postless distraction may be considered for patients at end ranges of height that exceed the limitations of common hip arthroscopy tables.

Preserving labral integrity has become a guiding principle in hip preservation surgery given the recent understanding of the importance of the acetabular labral suction seal. When labral tissue is deficient, a labral reconstruction may be indicated to re-create the suction seal and improve hip biomechanics. One of the main challenges of segmental labral reconstruction techniques is obtaining an accurate measurement of the defect because incorrect sizing of the graft could result in incomplete restoration of the labral seal or an oversized graft that requires amputation. In this report, we present a kite measurement technique that allows for easy, accurate measurement of the segmental defect during segmental labral reconstruction.

Questioning the routine use of postoperative laboratory tests is a strategy to combat rising health care costs. The goal of this study was to determine the utility and cost of routine postoperative complete blood count (CBC) testing after primary total knee arthroplasty (TKA) in the era of tranexamic acid (TXA). This retrospective chart review identified patients who underwent primary TKA performed by a single surgeon at a single private institution during a 2-year period. All patients received TXA intraoperatively. Exact tests were used to determine whether there was a significant difference in transfusion rates between patients with and without preoperative anemia. Of 628 primary TKA procedures, 390 patients (62.10%) had anemia postoperatively. However, only 1 patient (0.16%) required transfusion. A total of 956 CBC tests were performed without intervention, at a total cost of $116,804.08. In addition, 1 of 26 patients with preoperative anemia vs 0 of 602 patients without preoperative anemia required transfusion ( P =.04). Healthy patients undergoing primary TKA who receive TXA do not require postoperative CBC. This change has the potential to reduce this laboratory cost by more than 97% compared with the current practice of obtaining postoperative CBC testing for every patient undergoing TKA. Only patients with preoperative anemia should undergo postoperative CBC testing to help to identify those who require transfusion. The potential health care savings associated with eliminating routine postoperative CBC testing are substantial and should be considered by arthroplasty surgeons. [ Orthopedics . 2021;44(1):e26–e30.]

The meniscus plays an integral role in the knee with several unique functions, most notably to protect the chondral surfaces via load transmission and distribution. Given that meniscal integrity highly correlates with joint health, an awareness of meniscal anatomy and its insertions, meniscal biology, and meniscal biomechanics is paramount for the treating physician. This chapter will help the reader to better understand the (i) anatomy of the menisci with an emphasis on anatomic root attachments, (ii) microstructure and biology of meniscal tissue, and (iii) biomechanical properties of meniscal tissue and their clinical relevance following meniscal injury.

The purpose of this study was to evaluate the clinical results of surgical repair for proximal long head of the biceps (LHB) tendon ruptures comparing chronic primary and postsurgical revision LHB tendon ruptures. Patients who underwent subpectoral LHB tenodesis for chronic ruptures with a minimum of 2 years from surgery were identified. ASES and SF-12 PCS scores and surgical and demographic data were collected prospectively. At final follow-up, patients were interviewed regarding symptoms related to their biceps. Symptoms were converted into a Subjective Proximal Biceps Score (SPBS). Twenty-seven patients (22 males, 5 females) with a mean age of 61 years (range 40–76 years) underwent LHB tenodeses. Twenty patients (74.1 %) were primary repairs for chronic ruptures and seven patients (25.9 %) were revision repairs after failed prior LHB tenodesis. Twenty-five patients (92.6 %; n = 18 primary; n = 7 revision) were available for follow-up a mean of 3.8 years (range 2–6.1). The overall median postoperative SPBS showed significant improvement over the preoperative baseline (p

Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA-like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild-type (WT) mice were maintained on a constant 12 hour:12 hour LD cycle (12:12 LD) or exposed to weekly 12 hour phase shifts. Alternatively, male circadian mutant mice (ClockΔ19 or Csnk1etau mutants) were compared with age-matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix-degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ-ERK-RUNX2/NFκB and β-catenin signaling pathways, stimulation of MMP-13 and ADAMTS-5, as well as suppression of the anabolic mediators SOX9 and TIMP-3 in articular chondrocytes of phase-shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA-like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA-like pathological changes in the mouse knee joint.

Recovery of lower extremity muscular strength and neuromuscular control are two of the most vital aspects of anterior cruciate ligament (ACL) rehabilitation, as well as efforts to prevent noncontact ACL injury. There is strong evidence regarding the association between decreased hip range of motion, particularly internal and external rotation, and noncontact ACL injury. Given that females are at greater risk for ACL injury compared with males, increased emphasis has been placed on identifying risk factors in the hip as well as throughout the kinetic chain for this injury. In this chapter, we discuss the relationship between hip and knee injury patterns and its implications for ACL reconstruction and rehabilitation and noncontact ACL injury prevention efforts.

Background: Recent biomechanical evidence suggests that the meniscus-suture interface contributes the most displacement to the transtibial pull-out repair for meniscal root tears. Therefore, optimization of surgical technique at the meniscus-suture interface may minimize displacement and improve the strength of meniscal root repairs. Purpose/Hypothesis: The purpose of this study was to investigate the cyclic displacement and ultimate failure loads of 4 different meniscus-suture fixation techniques for posterior medial meniscal root repairs in human meniscus tissue. The hypothesis was that there would be no significant difference between the two simple sutures (TSS) technique and 3 other techniques in cyclic displacement or ultimate failure load. Study Design: Controlled laboratory study. Methods: A total of 32 fresh-frozen, human, medial meniscal transplant specimens were randomly assigned to 4 meniscus-suture fixation techniques used for transtibial pull-out repair in posterior medial meniscal root tears (n = 8 per group). The suture techniques studied were (1) TSS, (2) modified Mason-Allen (MMA), (3) single double-locking loop (S-DLL), and (4) double double-locking loop (D-DLL). The menisci were subjected to a cyclic tensioning protocol representative of postoperative rehabilitation (10-30 N for 1000 cycles) and pulled to failure at a rate of 0.5 mm/s. Results: After 1000 cycles, the TSS group displaced the least (mean ± SD, 1.78 ± 0.64 mm), followed by the MMA (2.14 ± 0.65 mm), D-DLL (2.97 ± 0.57 mm), and S-DLL (3.81 ± 0.78 mm) groups. After 100, 500, and 1000 cycles, suture displacements using the TSS and MMA techniques were not significantly different ( P > .13), while the TSS technique resulted in significantly less displacement than the S-DLL and D-DLL ( P < .03) techniques. The ultimate failure loads of the MMA (325 ± 77 N) and D-DLL (320 ± 50 N) techniques were significantly greater than those of the TSS (192 ± 52 N) and S-DLL (217 ± 51 N) techniques ( P < .05). Conclusion: The TSS and MMA fixation techniques were not significantly different, while the TSS was significantly better at resisting displacement when compared with the S-DLL and D-DLL stitch configurations. The MMA and D-DLL techniques exhibited significantly greater failure loads than did the TSS and S-DLL techniques; however, all techniques demonstrated ultimate failure loads above the currently accepted rehabilitation force threshold. Clinical Relevance: The TSS fixation technique combines the lowest technical difficulty and the ability to resist displacement at time zero. The MMA technique, although more technically challenging, may provide an alternative means to resist displacement while enhancing the failure load.

This paper presents the first reported case of iatrogenic injury to the anterior medial meniscal root attachment following intramedullary nailing for a tibial shaft fracture. The patient experienced a closed right tibia–fibula fracture 7 years prior to presentation, which was treated with a reamed intramedullary nail. The nail was removed 3 years after the index surgery due to chronic anterior knee pain, which persisted following hardware removal. At presentation, the patient was diagnosed with an anterior horn medial meniscal root tear likely secondary to insertion of the intramedullary nail through the anatomic footprint of the anterior medial root. After undergoing a medial meniscus anterior horn root repair, the patient was asymptomatic and resumed normal activities. Case report, Level IV.

Meniscal root tears, less common than meniscal body tears and frequently unrecognized, are a subset of meniscal injuries that often result in significant knee joint disorders. The meniscus root attachment aids meniscal function by securing the meniscus in place and allowing for optimal shock-absorbing function in the knee. With root tears, meniscal extrusion often occurs, and the transmission of circumferential hoop stresses is impaired. This alters knee biomechanics and kinematics and significantly increases tibiofemoral contact pressure. In recent years, meniscal root tears, which by definition include direct avulsions off the tibial plateau or radial tears adjacent to the root itself, have attracted attention because of concerns that significant meniscal extrusion dramatically inhibits normal meniscal function, leading to a condition biomechanically similar to a total meniscectomy. Recent literature has highlighted the importance of early diagnosis and treatment; fortunately, these processes have been vastly improved by advances in magnetic resonance imaging and arthroscopy. This article presents a review of the clinically relevant anatomic, biomechanical, and functional descriptions of the meniscus root attachments, as well as current strategies for accurate diagnosis and treatment of common injuries to these meniscus root attachments.

Osteoarthritis (OA) is characterized by a slow and progressive deterioration of articular cartilage. OA likely arises from a combination of systemic (genetics, age, environmental factors) and local factors (abnormal joint loading, overuse or trauma) working in concert to create a condition with definable morphologic and clinical characteristics. Several risk factors for OA have been previously identified, including genetic predisposition, obesity, diabetes, hypertension, hyperuricemia, previous trauma, and aging (1). However, due in large part to an inability to control for confounding factors, the underlying pathogenesis and causative factors responsible for initiation and progression of the disease remain largely unknown. There is a growing body of evidence correlating progression of OA with an upregulation of inflammatory processes (2). Oxidative stress elicited by reactive oxygen species (ROS) further disturbs cartilage homeostasis and promotes catabolism via induction of cell death, breakdown of matrix proteoglycans (PGs), upregulation of latent matrix-degrading enzyme production, inhibition of extracellular matrix (ECM) synthesis, and oxidation of intracellular and extracellular molecules (3). Thus, environmental factors that promote oxidative stress and inflammatory states could potentially act as a risk factor for OA. Alcohol consumption could be one potential risk factor because: [1] chronic alcohol consumption, highly common in Western and industrial societies, generates reactive oxygen species (ROS), leading to systemic and tissue oxidative stress in human and rodents, and [2] alcohol is capable of inducing pro-inflammatory states in multiple organs such as liver, heart, central nervous system, and pancreas (4, 5). Several studies have previously attempted to elucidate a relationship between alcohol consumption and inflammatory arthritis such as rheumatoid arthritis, with conflicting results (6, 7). However, despite recent evidence demonstrating the importance of oxidative stress and pro-inflammatory states in the development and progression of degenerative joint disease, the impact of alcohol consumption on OA has not yet been studied. The findings of the present study suggest that chronic alcohol exposure may increase susceptibility to the development and/or progression of OA. Using a validated in vivo model of chronic alcohol treatment, we show that chronic alcohol consumption increases PG loss in both knee and shoulder joints of mice, stimulates multiple inflammatory, catabolic, and anti-anabolic mediators involved in cartilage. In our experimental protocol, young adult male (aged 7–9 weeks) C57BL/6 mice were provided ad libitum access to an alcohol-diet (i.e., the Nanji diet), containing 4.5% (v/v) ethanol (29% ethanol-derived calories) or an isocaloric alcohol-free control diet for 8 weeks (n=14–16 per group). All animal protocols and practices were reviewed and approved in advance by the Institutional Animal Care and Use Committees at Rush University and Northwestern University. Following eight weeks of alcohol-containing diet or the control diet, mice were euthanized and joint sections were collected, fixed, paraffin-embedded, and stained with Safranin-O to assess cartilage structure and matrix proteoglycan (PG) content. The alcohol diet is a slight modification of the well-validated Leiber-DiCarli diet in which the fat source comes from fish oil and consumption of this diet in BL6 mice has been shown to produce blood alcohol levels that are in the low to moderate level (8). Our group, and others, have successfully used this alcohol diet to induce a variety of alcohol pathologies including colon cancer, intestinal hyperpermeability, endotoxemia, and liver pathology in rodents (8–10). Serum alcohol level in the alcohol-fed mice at the time of euthanasia was ~3mg/dL and these mice did not show any overt behavioral abnormalities during our experimental protocol. Histological examination of knee joints of control diet-fed mice demonstrated normal architecture of articular cartilage with intense Safranin-O staining. In contrast, knee joints of alcohol-fed mice displayed OA-like characteristics, with increases in PG loss represented by Safranin-O staining and mild fibrillation (Figure 1A). These results were quantified using an OARSI semi-quantitative scoring system. Alcohol-fed mice scored significantly higher (1.3±0.67) than control mice (0.3±0.27; P < 0.05), indicating more severe arthritic changes in knee joints of alcohol-fed mice compared to control (Figure 1A, lower panel). Similar results were found in shoulder joints (Figure 1B), as Safranin-O staining revealed a decrease in gross PG content and an irregular cartilage surface in shoulder joints of alcohol-fed mice compared to the control group. We applied the OARSI scoring to quantify pathological changes in shoulder, and found significantly higher OARSI scores for alcohol-fed mice (0.75±0.28) compared to control mice (0.12±0.25; P < 0.05) (Figure 1B, lower panel). Interestingly, the intervertebral discs showed no pathological changes in alcohol-fed mice compared to control mice (Figure 1C). Figure 1 Chronic ethanol consumption induces pathological changes in articular cartilage Our results demonstrate a pathologic role of alcohol on specific catabolic and anti-anabolic mediators in knee joints (Supplemental Figure 1) that may increase susceptibility of OA induction. In our study, phospho protein kinase C δ (pPKCδ), pNF-κB, and pERK1/2 were significantly increased in knee joints of alcohol-fed compared to control mice (Supplemental Figure 1A, P < 0.05), suggesting that chronic alcohol consumption stimulates these catabolic signaling pathways, which may result in subsequent production of cartilage destructive enzymes. Hypertrophic marker RUNX2, as well as a key cartilage destructive enzymes matrix metalloprotease- 13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), were significantly increased in knee joints of alcohol-fed mice compared to the control mice (Supplemental Figure 1B; P < 0.05). In addition to induction of catabolic effects, we observed that chronic alcohol consumption resulted in a striking reduction of anabolic and anti-inflammatory mediators in articular chondrocytes as assessed by immunohistochemistry (Supplemental Figure 1C, P < 0.05). These molecules include tissue inhibitor of metalloproteinase-3 (TIMP-3), SOX-9, high-mobility group protein-2 (HMGB2) and suppressor of cytokine signaling-2 (SOCS-2), molecules that were significantly decreased in OA cartilage and associated with both cartilage protection and repair. These findings clearly demonstrate that chronic alcohol consumption augments catabolic signaling pathways and suppresses anabolic, reparative, and anti-inflammatory activity in mouse knee articular chondrocytes. We also performed micro-computed tomography (uCT) to determine whether any pathological changes in bone pathology after chronic alcohol treatment were evident. However, we did not find significant bone pathology in the knee-joints of alcohol-fed mice from our experimental protocol (data not shown). To our knowledge, these findings provide the first evidence that chronic alcohol consumption may be a novel risk factor for the development of OA. The pathology associated with chronic alcohol consumption is multi-factorial, with diverse consequences in different cell types through direct toxic effects as well as indirect effects of specific metabolites, oxidative stress, immunologic/inflammatory processes. It is well-established that alcohol consumption causes endotoxemia that is thought to contribute to alcohol liver damage (11). Indeed, we have shown that alcohol consumption promotes intestinal hyperpermeability and endotoxemia in rodents including BL6 mice (8) phenomenon that are also observed in human alcoholics (12). Future studies are necessary to evaluate the contribution of intestinal barrier dysfunction and endotoxemia in our studies. There are, however, several limitations of this study that need to be mentioned. First, we have addressed the effects of chronic alcohol consumption in an in vivo mouse model of the knee joint, which makes it difficult to generalize results across species to human joint tissue. Clinical studies are necessary to confirm our data to associate chronic alcoholism and joint pathology. Second, the current study reports the potent catabolic activity of chronic alcohol in cartilage homeostasis via PKCδ, and MAPK signaling, but a detailed understanding of the specific cell signaling pathways and molecular mechanisms underlying these findings remains to be elucidated. Finally, although these results have significant potential clinical relevance, several aspects of the underlying mechanisms remain unknown. Further studies will facilitate a better understanding of the multiple, complex effects stimulated by alcohol in joint tissue.

Purpose To analyze the current practice patterns of non-arthroplasty treatment of knee osteoarthritis (OA) and to assess the impact of the American Academy of Orthopaedic Surgeons clinical practice guidelines on the management of OA of the knee, particularly as they relate to the use of arthroscopic treatment. Methods The United Healthcare Database (2004-2009, 11 million patients, 216 million records) was used for the study and was searched using Boolean language for International Classification of Diseases, Ninth Edition, Clinical Modification and Current Procedural Terminology, fourth revision codes. A reference group was defined as patients treated with knee arthroplasty in 2009 and diagnosed with knee OA in the same record. Clinical practice patterns in the 5 years preceding arthroplasty were analyzed in this group. Results The reference group consisted of 12,806 patients undergoing total knee arthroplasty in 2009 with a documented diagnosis of OA at the time of surgery, with prior nonoperative treatment strategies analyzed during the preceding 5 years (2004-2009); 10.0% of patients were prescribed physical therapy specific to OA, 2.6% received an unloader brace, 0.52% underwent acupuncture, 43.5% were administered intra-articular corticosteroids, and 15.4% received viscosupplementation injections. During the 5 years before arthroplasty, 2,505 patients (19.6%) underwent arthroscopy and debridement/lavage, 35% of whom did not have a diagnosis code for mechanical pathology. Within 1 year of knee arthroplasty, 2,028 of the 2,505 knee arthroscopies (80.9%) were performed. Conclusions The findings show that significant gaps do exist between the evidence-based American Academy of Orthopaedic Surgeons recommendations and actual practice patterns in the United States between 2004 and 2009. Level of Evidence Level IV, diagnostic study.

Bovine lactoferricin (LfcinB) is a multifunctional peptide derived from bovine lactoferrin that demonstrates antibacterial, antifungal, antiviral, antitumor, and immunomodulatory activities. Recently, studies have focused on the anti-catabolic and anti-inflammatory potential of LfcinB. LfcinB is able to modulate the effects cytokines such as IL-1 and fibroblast growth factor 2 as well as promote specific cartilage anabolic factors. These properties are particularly important in maintaining cartilage homeostasis and preventing a catabolic state, which leads to clinical pathology. This review focuses on the recent literature elucidating the role of LfcinB in preventing cartilage degradation.

Bone-morphogenetic protein-7 (BMP7) is a well-known anabolic and anti-catabolic growth factor on intervertebral disc (IVD) matrix and cell homeostasis. Similarly, Lactoferricin B (LfcinB) has recently been shown to have pro-anabolic, anti-catabolic, anti-oxidative and/or anti-inflammatory effects in bovine disc cells in vitro. In this study, we investigated the potential benefits of using combined peptide therapy with LfcinB and BMP7 for intervertebral disc matrix repair and to understand cellular and signaling mechanisms controlled by these factors. We studied the effects of BMP7 and LfcinB as individual treatments and combined therapy on bovine nucleus pulposus (NP) cells by assessing proteoglycan (PG) accumulation and synthesis, and the gene expression of matrix protein aggrecan and transcription factor SOX-9. We also analyzed the role of Noggin, a BMP antagonist, in IVD tissue and examined its effect after stimulation with LfcinB. To understand the molecular mechanisms by which LfcinB synergizes with BMP7, we investigated the ERK-SP1 axis as a downstream intracellular signaling regulator involved in BMP7 and LfcinB-mediated activities. Treatment of bovine NP cells cultured in alginate with LfcinB plus BMP7 synergistically stimulates PG synthesis and accumulation in part by upregulation of aggrecan gene expression. The synergism results from LfcinB-mediated activation of Sp1 and SMAD signaling pathways by (i) phosphorylation of SMAD 1/5/8; (ii) downregulation of SMAD inhibitory factors [i.e., noggin and SMAD6 (inhibitory SMAD)]; and (iii) upregulation of SMAD4 (universal co-SMAD). These data indicate that LfcinB-suppression of Noggin may eliminate the negative feedback of BMP7, thereby maximizing biological activity of BMP7 and ultimately shifting homeostasis to a pro-anabolic state in disc cells. We propose that combination growth factor therapy using BMP7 and LfcinB may be beneficial for treatment of disc degeneration.

Although the merits of labral reconstruction have been well established, the technical difficulty of presently used reconstruction techniques—particularly with graft passage and fixation—limit its efficacy and potentiates the risk of iatrogenic damage within the hip joint. The unwieldy nature of a floating labral graft anchored on one end may impede accurate fixation of the other end, which is critical for restoration of the fluid hip seal and preservation of graft integrity. In this technique narrative, we present a “kite technique” for introduction, control, and efficient fixation of a labral reconstruction graft. The principles of this method are founded on the belief that a soft-tissue graft in an arthroscopic environment is much easier to guide into position with 2 control sutures using a pulley system similar to flying a kite with 2 fly lines. Although we herein detail the technique as it applies to labral reconstruction in the hip, the concept of the kite technique may also be employed in arthroscopic-assisted soft-tissue reconstructions of other joints.

MyD88 is an adapter protein that links toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs) with downstream signaling molecules. The MyD88 has been found to be an essential mediator in the development of osteoarthritis in articular cartilage. However, the role of the MyD88 pathway has yet to be elucidated in the intervertebral disk (IVD). Using in vitro techniques, we analyzed the effect of MyD88 pathway-specific inhibition on the potent inflammatory and catabolic mediator LPS and IL-1 in bovine and human nucleus pulposus (NP) cells by assessing matrix-degrading enzyme expression, including matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family). We also analyzed inhibition of MyD88 in the regulation of inducible nitric oxide synthase and TLR-2. Finally, we used an ex vivo organ culture model to assess the effects of MyD88 inhibitor (MyD88i) on catabolic factor-induced disk degeneration in mice lumbar disks. In bovine NP cells, MyD88i potently antagonizes LPS- or IL-1-mediated induction of cartilage-degrading enzyme production, including MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5. MyD88i also attenuates the LPS- or IL-1-mediated induction of iNOS and TLR-2 gene expression. Our ex vivo findings reveal inhibition of MyD88 via counteraction of IL-1-mediated proteoglycan depletion. The findings from this study demonstrate the potent anti-inflammatory and anti-catabolic effects of inhibition of MyD88 pathway inhibition on IVD homeostasis, suggesting a potential therapeutic benefit of a MyD88i in degenerative disk disease in the future.

Anterior cruciate ligament (ACL) reconstruction is a technically challenging procedure with a multitude of steps. As the most common cause of ACL failure is poor surgical technique, avoiding problems before they occur is paramount. Graft-tunnel mismatch is one such problem that can occur due to donor anatomy or poor surgical technique. Here we review common causes and solutions with regard to graft-tunnel mismatch during ACL reconstruction.

Existing literature demonstrates that fibroblast growth factor-2 (FGF-2) exerts opposing, contradictory biological effects on cartilage homeostasis in different species. In human articular cartilage, FGF-2 plays a catabolic and anti-anabolic role in cartilage homeostasis, driving homeostasis toward degeneration and osteoarthritis (OA). In murine joints, however, FGF-2 has been identified as an anabolic mediator as ablation of the FGF-2 gene demonstrated increased susceptibility to OA. There have been no previous studies specifically addressing species-specific differences in FGF-2-mediated biological effects. In this study, we provide a mechanistic understanding by which FGF-2 exerts contradictory biological effects in human versus murine tissues. Using human articular cartilage (ex vivo) and a medial meniscal destabilization (DMM) animal model (in vivo), species-specific expression patterns of FGFR receptors (FGFRs) are elucidated between human and murine articular cartilage. In the murine OA model followed by intra-articular injection of FGF-2, we further correlate FGFR profiles to changes in behavioral pain perception, proteoglycan content in articular cartilage, and production of inflammatory (CD11b) and angiogenic (VEGF) mediators in synovium lining cells. Our results suggest that the fundamental differences in cellular responses between human and murine tissues may be secondary to distinctive expression patterns of FGFRs that eventually determine biological outcomes in the presence of FGF-2. The complex interplay of FGFRs and the downstream signaling cascades induced by FGF-2 in human cartilage should add caution to the use of this particular growth factor for biological therapy in the future.

Objective We undertook this study to assess the therapeutic benefits of intervertebral disc matrix repair and regeneration by evaluating the potential synergistic effect of insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein 7 (BMP-7) on bovine spine discs and by elucidating the relevant molecular/cellular mechanisms. Methods Bovine nucleus pulposus (NP) cells were treated with BMP-7 and IGF-1. The subsequent anabolic effects driven by NP cells were assessed for proteoglycan (PG) synthesis by 35S-sulfate incorporation and for PG accumulation by dimethylmethylene blue assays. Matrix formation was visualized by particle exclusion assay. Key matrix components and transcription factors were analyzed by real-time reverse transcription–polymerase chain reaction to determine the signaling pathways by which IGF-1 suppresses noggin, a potent inhibitor of BMP-7. Western blotting and nuclear translocation experiments were performed to assess the activation of Smad proteins. Results Stimulation of bovine NP cells by both IGF-1 and BMP-7 greatly potentiated anabolism through complementary and synergistic mechanisms on matrix formation compared with treatment with either growth factor alone. The exogenously added decoy ligand, noggin, attenuated the anabolic effects of BMP-7, and noggin was substantially increased by BMP-7, suggesting a negative feedback regulatory mechanism. In contrast, IGF-1 significantly suppressed noggin expression via the phosphatidylinositol 3-kinase/Akt pathway and thus potentiated BMP-7 signaling in bovine NP cells. Upon combination treatment, IGF-1 activated Smad2, while BMP-7 activated Smad1/5/8 and Smad3, thus inducing all Smad signaling pathways and mimicking the effects of the combination of transforming growth factor β and BMP-7 Conclusion Combination growth factor therapy using BMP-7 and IGF-1 may have considerable promise in the treatment of spine disc degeneration.

Objective To elucidate the pathophysiologic links between prostaglandin E2 (PGE2) and osteoarthritis (OA) by characterizing the catabolic effects of PGE2 and its unique receptors in human adult articular chondrocytes. Methods Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE2 and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription–polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. Results Stimulation of human articular chondrocytes with PGE2 through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE2 titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE2 or an EP2 receptor–specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. Conclusion PGE2 exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA.

Two members of the fibroblast growth factor (FGF) family, basic FGF (bFGF) and FGF-18, have been implicated in the regulation of articular and intervertebral disc (IVD) cartilage homeostasis. Studies on bFGF from a variety of species have yielded contradictory results with regards to its precise role in cartilage matrix synthesis and degradation. In contrast, FGF-18 is a well-known anabolic growth factor involved in chondrogenesis and articular cartilage repair. In this review, we examined the biological actions of bFGF and FGF-18 in articular and IVD cartilage, the specific cell surface receptors bound by each factor, and the unique signaling cascades and molecular pathways utilized to exert their biological effects. Evidence suggests that bFGF selectively activates FGF receptor 1 (FGFR1) to exert degradative effects in both human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme activity, inhibition of matrix production, and increased cell proliferation resulting in clustering of cells seen in arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating FGFR3, increasing matrix formation and cell differentiation while inhibiting cell proliferation, leading to dispersed cells surrounded by abundant matrix. The results from in vitro and in vivo studies suggest the potential usefulness of bFGF and FGFR1 antagonists, as well as FGF-18 and FGFR3 agonists, as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future.

Pain-related neuropeptides released from synovial fibroblasts, such as substance P, have been implicated in joint destruction. Substance P-induced inflammatory processes are mediated via signaling through a G-protein-coupled receptor, that is, neurokinin-1 tachykinin receptor (NK(1)-R). We determined the pathophysiological link between substance P and its receptor in human adult articular cartilage homeostasis. We further examined if catabolic growth factors such as basic fibroblast growth factor (bFGF or FGF-2) or IL-1beta accelerate matrix degradation via a neural pathway upregulation of substance P and NK(1)-R. We show here that substance P stimulates the production of cartilage-degrading enzymes, such as matrix metalloproteinase-13 (MMP-13), and suppresses proteoglycan deposition in human adult articular chondrocytes via NK(1)-R. Furthermore, we have demonstrated that substance P negates proteoglycan stimulation promoted by bone morphogenetic protein-7, suggesting the dual role of substance P as both a pro-catabolic and anti-anabolic mediator of cartilage homeostasis. We report that bFGF-mediated stimulation of substance P and its receptor NK(1)-R is, in part, through an IL-1beta-dependent pathway.

In athletes, significant advances in anterior cruciate ligament reconstruction techniques and rehabilitation have led to improved surgical outcomes and increased expectations for return to play. Although an expeditious return to sport has become an achievable and often realistic goal, the factors that most influence safe, timely, and successful return to play remain unknown. The literature offers mainly anecdotal evidence to guide the team physician in the decision-making process, with a paucity of criteria and consensus guidelines available to help determine return to sport. Attempts have been made to introduce criteria-based progression in the rehabilitation process, but validation of subjective and objective criteria has been difficult. Nevertheless, several pertinent factors in the preoperative, intraoperative, and postoperative periods may affect return to play following anterior cruciate ligament reconstruction. Further research is warranted to validate reliable, consensus guidelines with objective criteria to facilitate the return to play process.

Background: Intramedullary (IM) nailing is the treatment of choice among orthopaedic surgeons for tibial shaft fractures. However, because of the close proximity of the nail’s insertion site to the anterior medial (AM) meniscal root on the tibial plateau, there is increased risk of iatrogenic injury to the meniscal root during nailing. Purpose: To quantify the area of the AM meniscal root footprint damaged by IM tibial reaming and determine its subsequent effects on the ultimate failure load in female versus male knees. Study Design: Controlled laboratory study. Methods: Twelve matched pairs (6 male and 6 female pairs; average age, 50.2 years) of human cadaveric knees were randomly assigned to native and reamed groups. In the reamed group, knees were reamed within the “safe zone” according to current guidelines for IM tibial nail insertion (3 mm lateral to the center of the tibial tubercle and adjacent to the anterior margin of the tibial plateau). The attachment areas and ultimate failure load were quantified and compared with paired knees in the native group. Results: Intra-articular reaming within the “safe zone” for IM tibial nail insertion did not significantly decrease the AM root attachment area or ultimate failure load in male specimens, as only 2 of the 6 knees were damaged by reaming. In contrast, all 6 of the AM roots in the female knees were damaged by reaming, and on average, reaming decreased the female AM root attachment area by 19% and significantly decreased ultimate failure load by 37% ( P = .028). There was a strong negative correlation ( R2 = 0.77) between reamed tunnel–AM root overlap area and medial-lateral width in female but not in male knees. Conclusion: Standard reaming for an IM tibial nail induced significant damage to the AM meniscal root in smaller, female specimens, whereas larger, male specimens were not affected. Clinical Relevance: These findings may suggest that improvements in current guidelines and surgical techniques are warranted to prevent iatrogenic injury to the AM meniscal root during intramedullary reaming for tibial shaft fractures in females and in smaller patients.

Background: The tibial tubercle–trochlear groove (TTTG) distance is used to quantify the degree of lateralization of the patellar tendon insertion on the tibial tubercle relative to the deepest part of the trochlear groove. Disagreement exists as to whether the TTTG distance measured on computed tomography (CT) and magnetic resonance imaging (MRI) can be considered equivalent. Purpose: To compare TTTG distance as measured on axial CT and MRI and to investigate the potential effect of patient positioning between modalities. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Patients who received both CT and MRI of the same knee for any indication from August 2010 to April 2014 were included in this study. The TTTG distances were measured twice by 2 raters in a randomized order, with at least 30 days between ratings to minimize recall bias. Inter- and intrarater reliability of CT and MRI measurements and intermethod reliability were assessed with intraclass correlation coefficients (ICCs). Bland-Altman plots were also created to assess agreement. Differences in patient positioning were investigated to determine its effect on the TTTG distance. Results: Fifty-nine patients (age, 32.8 ± 12.9 years) were included. Interrater ICCs were excellent for both CT and MRI measurements. Intrarater ICCs were excellent for both raters. Absolute agreement ICCs for intermethod reliability were fair to good, but consistency type agreement was excellent. A systematic bias of lower MRI distances (bias = −2.8 mm) compared with CT was observed. The investigation of CT versus MRI imaging techniques demonstrated that the standard MRI examination places the knee in approximately 4.6° of relative varus alignment compared with CT. Conclusion: A systematic bias toward lower TTTG distances on MRI compared with CT was found. This finding is likely dependent on imaging technique, including patient positioning. Patient knees were positioned in varus on the MRI compared with the CT examination, with resulting lower TTTG distances on MRI compared with CT. The TTTG distances on CT and MRI vary with imaging technique, which may be attributable to patient positioning and result in differences among imaging centers.

Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA-like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild-type (WT) mice were maintained on a constant 12 hour:12 hour LD cycle (12:12 LD) or exposed to weekly 12 hour phase shifts. Alternatively, male circadian mutant mice (ClockΔ19 or Csnk1etau mutants) were compared with age-matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix-degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ-ERK-RUNX2/NFκB and β-catenin signaling pathways, stimulation of MMP-13 and ADAMTS-5, as well as suppression of the anabolic mediators SOX9 and TIMP-3 in articular chondrocytes of phase-shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA-like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA-like pathological changes in the mouse knee joint.

Background: A common treatment for posterior meniscal root tears is transtibial pull-out repair, which has been biomechanically reported to restore tibiofemoral contact mechanics to those of the intact knee. Biomechanical data suggest that there is significant displacement of the repaired meniscal root with cyclic loading, which may be responsible for the poor healing and meniscal extrusion demonstrated in some clinical studies. Hypothesis/Purpose: The purpose of this study was to quantify the time-zero displacement of the posterior meniscal root in response to cyclic loading after transtibial pull-out repair and to quantify the individual contributions to displacement of the following: (1) suture elongation, (2) button-bone interface, and (3) meniscus-suture interface. The meniscus-suture interface was hypothesized to result in significantly more displacement than the button-bone interface or suture elongation. Study Design: Descriptive laboratory study. Methods: Transtibial pull-out repair of the posterior medial meniscal root was performed in 6 porcine knees, and cyclic displacement was measured using a loading protocol representative of postoperative rehabilitation. Displacement from (1) suture elongation, (2) the button-bone interface, and (3) the meniscus-suture interface was determined by cyclically loading 6 specimens for each construct using the same loading protocol to determine the contribution of each component to the overall displacement of the repair construct. Results: After 1000 cycles, the repair construct displaced by a mean of 3.28 mm (95% CI, 2.07-4.49). The meniscus-suture component (mean, 2.52 mm; 95% CI, 2.21-2.83) displaced significantly more than the button-bone component (mean, 0.90 mm; 95% CI, 0.64-1.15; P = .006) and suture elongation component (mean, 0.71 mm; 95% CI, 0.36-1.06; P = .006) after 1000 cycles. Displacement of the button-bone and suture elongation components was not significantly different after 1000 cycles ( P = .720). Conclusion: There was substantial displacement of the posterior medial meniscal root repaired with the transtibial pull-out technique under a cyclic loading protocol simulating postoperative rehabilitation. The meniscus-suture interface contributed to significantly more displacement than the button-bone interface and suture elongation in the transtibial pull-out repair construct. Clinical Relevance: The results provide a framework for optimizing the transtibial pull-out repair technique. Future studies should focus on improving suture fixation strength within the meniscus-suture interface.

Background: Anatomic root placement is necessary to restore native meniscal function during meniscal root repair. Radiographic guidelines for anatomic root placement are essential to improve the accuracy and consistency of anatomic root repair and to optimize outcomes after surgery. Purpose: To define quantitative radiographic guidelines for identification of the anterior and posterior root attachments of the medial and lateral menisci on anteroposterior (AP) and lateral radiographic views. Study Design: Descriptive laboratory study. Methods: The anterior and posterior roots of the medial and lateral menisci were identified in 12 human cadaveric specimens (average age, 51.3 years; age range, 39-65 years) and labeled using 2-mm radiopaque spheres. True AP and lateral radiographs were obtained, and 2 raters independently measured blinded radiographs in relation to pertinent landmarks and radiographic reference lines. Results: On AP radiographs, the anteromedial and posteromedial roots were, on average, 31.9 ± 5.0 mm and 36.3 ± 3.5 mm lateral to the edge of the medial tibial plateau, respectively. The anterolateral and posterolateral roots were, on average, 37.9 ± 5.2 mm and 39.3 ± 3.8 mm medial to the edge of the lateral tibial plateau, respectively. On lateral radiographs, the anteromedial and anterolateral roots were, on average, 4.8 ± 3.7 mm and 20.5 ± 4.3 mm posterior to the anterior margin of the tibial plateau, respectively. The posteromedial and posterolateral roots were, on average, 18.0 ± 2.8 mm and 19.8 ± 3.5 mm anterior to the posterior margin of the tibial plateau, respectively. The intrarater and interrater intraclass correlation coefficients (ICCs) were >0.958, demonstrating excellent reliability. Conclusion: The meniscal root attachment sites were quantitatively and reproducibly defined with respect to anatomic landmarks and superimposed radiographic reference lines. The high ICCs indicate that the measured radiographic relationships are a consistent means for evaluating meniscal root positions. Clinical Relevance: This study demonstrated consistent and reproducible radiographic guidelines for the location of the meniscal roots. These measurements may be used to assess root positions on intraoperative fluoroscopy and postoperative radiographs.

Background: While the biomechanical importance of the meniscal roots has been demonstrated, the anatomy of the anterior meniscal roots remains largely unknown. Defining the quantitative anatomy of the anterior meniscal root attachments is essential for developing improved diagnostic and surgical techniques. Hypothesis: The anterior medial (AM) and anterior lateral (AL) meniscal roots could be quantitatively defined relative to open and arthroscopic surgical landmarks. Study Design: Descriptive laboratory study. Methods: Twelve nonpaired human cadaveric knees were used (average age, 51.3 years). A coordinate measuring device quantified the anatomic relationships of the AM and AL root attachments to open and arthroscopic surgical landmarks. The tibial attachments of both anterior roots were defined and quantified by categorizing the fibers of the root as either central, dense attachments or peripheral, supplemental attachments. Results: The center of the tibial tuberosity and the medial tibial eminence apex were 27.0 mm lateral and distal and 27.5 mm posterior to the center of the AM root, respectively. The center of the anterior cruciate ligament (ACL) and the lateral tibial eminence apex were 5.0 mm posteromedial and 14.4 mm posterolateral to the center of the AL root, respectively. The AM root attachment had a mean area of 110.4 mm2 (95% CI, 92.2-128.5) with a central attachment of 56.3 mm2 (95% CI, 46.9-65.8). The AL root attachment had a mean area of 140.7 mm2 (95% CI, 121.6-159.8) and inserted deeply beneath the ACL in all specimens. The overlap of the ACL on the AL root averaged 88.9 mm2 (95% CI, 63.3-114.6), comprising 63.2% of the AL root attachment. Conclusion: The anterior meniscal roots were identified in relation to pertinent open and arthroscopic landmarks. The extended overlap between the AL root and ACL attachment revealed a more intimate tibial attachment relationship than previously recognized. Clinical Relevance: Quantitative descriptions of the anterior meniscal roots elucidate the relationship between the root attachments and pertinent surgical landmarks. In addition, the supplemental attachments of both menisci may contribute to native meniscal function, and further investigation is recommended.

Background: Current surgical techniques for meniscal root repair reattach the most prominent, dense portion of the meniscal root and fail to incorporate recently identified peripheral, supplemental attachment fibers. The contribution of supplemental fibers to the biomechanical properties of native meniscal roots is unknown. Hypothesis/Purpose: The purpose was to quantify the ultimate failure strengths, stiffness, and attachment areas of the native posterior medial (PM), posterior lateral (PL), anterior medial (AM), and anterior lateral (AL) meniscal roots compared with the most prominent, dense meniscal root attachment after sectioning of supplemental fibers. It was hypothesized that the ultimate failure strength, stiffness, and attachment area of each native root would be significantly higher than those of the respective sectioned root. Study Design: Controlled laboratory study. Methods: Twelve matched pairs of male human cadaveric knees were used. The 4 native meniscal roots were left intact in the native group, whereas the roots in the contralateral knee (sectioned group) were dissected free of all supplemental fibers. A coordinate measuring device quantified the amount of tissue resected in the sectioned group compared with the native group. A dynamic tensile testing machine pulled each root in line with its circumferential fibers. All root attachments were preconditioned from 10 to 50 N at a rate of 0.1 Hz for 10 cycles and subsequently pulled to failure at a rate of 0.5 mm/s. Results: Supplemental fibers composed a significant percentage of the native PM, PL, and AM meniscal root attachment areas. Mean ultimate failure strengths (in newtons) of the native PM, PL, and AM roots were significantly higher than those of the sectioned state, while the ultimate failure strength of the native AL root was indistinguishable from that of the sectioned state. Conclusion: Three of the 4 meniscal root attachments (PM, PL, AM) contained supplemental fibers that accounted for a significant percentage of the native root attachment areas, and these fibers significantly contributed to the failure strengths of the native roots. Clinical Relevance: These supplemental fibers are not routinely reattached during root repair surgery, suggesting that current techniques fail to reattach the biomechanically relevant attachments of native meniscal roots.

Corrigenda and errata concerning the article by Michael Ellman, ‘Stalin and the Soviet famine of 1932-33 revisited

The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production, and enzyme activity in long-term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL-6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future.