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Background: Though articular cartilage stem cell (ACSC)-based therapies have been demonstrated to be a promising option in the treatment of diseased joints, the wide variety of cell isolation, the unknown therapeutic targets, and the incomplete understanding of the interactions of ACSCs with diseased microenvironments have limited the applications of ACSCs., Methods: In this study, the human ACSCs have been isolated from osteoarthritic articular cartilage by advantage of selection of anatomical location, the migratory property of the cells, and the combination of traumatic injury, mechanical stimuli and enzymatic digestion. The protective effects of ACSC infusion into osteoarthritis (OA) rat knees on osteochondral tissues were evaluated using micro-CT and pathological analyses. Moreover, the regulation of ACSCs on osteoarthritic osteoclasts and the underlying mechanisms in vivo and in vitro were explored by RNA-sequencing, pathological analyses and functional gain and loss experiments. The one-way ANOVA was used in multiple group data analysis., Results: The ACSCs showed typical stem cell-like characteristics including colony formation and committed osteo-chondrogenic capacity. In addition, intra-articular injection into knee joints yielded significant improvement on the abnormal subchondral bone remodeling of osteoarthritic rats. Bioinformatic and functional analysis showed that ACSCs suppressed osteoarthritic osteoclasts formation, and inflammatory joint microenvironment augmented the inhibitory effects. Further explorations demonstrated that ACSC-derived tumor necrosis factor alpha-induced protein 3 (TNFAIP3) remarkably contributed to the inhibition on osteoarhtritic osteoclasts and the improvement of abnormal subchondral bone remodeling., Conclusion: In summary, we have reported an easy and reproducible human ACSC isolation strategy and revealed their effects on subchondral bone remodeling in OA rats by releasing TNFAIP3 and suppressing osteoclasts in a diseased microenvironment responsive manner., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are unknown., Purpose: To determine whether the timing of mechanical loading and ALN influences the pathobiological changes of OA., Study Design: Controlled laboratory study., Methods: Mice with OA induced by anterior cruciate ligament transection were subjected to early (1-3 weeks) or late (5-7 weeks) axial compressive dynamic load or intraperitoneal injection of ALN. Changes in gait were analyzed using gait analysis system, pathobiological changes in subchondral bone, cartilage, osteophyte, and synovitis were assessed using micro-computed tomography, tartrate-resistant acid phosphatase staining, pathologic section staining, and immunohistochemistry at 1, 2, 4, and 8 weeks., Results: At 1, 2, and 4 weeks, the OA limb had lower mean footprint pressure intensity, lower bone volume per tissue volume (BV/TV) in the subchondral bone, and more osteoclasts. At 4 weeks, the early loading, ALN, and load + ALN treatments induced less cartilage destruction, with a corresponding reduction in Osteoarthritis Research Society International score and increased hyaline cartilage thickness. The treatments also resulted in fewer osteoclasts and higher BV/TV and bone mineral density of subchondral bone and suppressed inflammation and interleukin 1β- and tumor necrosis factor α-positive cells in synovium. At 8 weeks, early loading or load + ALN improved the mean footprint pressure intensity and knee flexion. At 8 weeks, early load + ALN had a synergistic effect on protecting hyaline cartilage and proteoglycans. Footprint pressure intensity and cartilage destruction were worse in late loading limbs, and no differences in BV/TV, bone mineral density, osteophyte formation, and synovium inflammation were found between the late load, ALN, and load + ALN groups and the anterior cruciate ligament transection group., Conclusion: Dynamic axial mechanical loading or ALN in the early stages of knee trauma protected against OA by suppressing subchondral bone remodeling. However, late loading promoted cartilage degeneration in advanced OA, indicating that reduced loading should be performed in the late stages of OA to avoid the acceleration of OA., Clinical Relevance: Early low-level functional exercise or antiosteoporotic drugs could clearly slow or prevent the progression of early OA. For patients with mild to severe OA, loading reduction via brace protection or maintenance of joint stability via early ligament reconstruction surgery may ameliorate OA exacerbation.

Objective: To investigate the effect of intra-articular berberine injection on the structural remodeling of subchondral bone plate and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand(OPG/RANKL) system expression in rabbits with osteoarthritis(OA)., Methods: Forty 12-month-old male rabbits with an average of(2.73±0.18) kg of body weight, underwent left anterior cruciate ligament transection(ACLT), and were divided into berberine group and placebo groups after operation, 20 rabbits in each group. The berberine group received intra-articular injection of 100 μmol/L berberine 0.3 ml every week for 6 weeks. In placebo group, the same dose of 0.9% sodium chloride injection was injected into the left knee joint cavity every week for 6 weeks. Another 20 12-month-old male rabbits, weighing (2.68±0.18) kg, underwent sham operation on the left knee joint without intra-articular injection intervention (sham operation group). On the last day of the sixth week after operation, three groups of animals were sacrificed to obtain knee joint specimens. The femoral medial condyle samples were obtained for histological evaluation of cartilage and subchondral bone, Mankin scoring system was used to evaluate articular cartilage structure. Image-Pro Plus(IPP) software was used to evaluate subchondral bone plate bone volume(BV), bone volume/total volume(BV/TV), trabecular circumference(TC), mean trabecular thickness (Tb.Th). Real-time quantitative reverse transcription polymerization Enzyme chain reaction(reverse transcription-polymerase chain reaction, RT-PCR) was used to detect the mRNA expression levels of OPG and RANKL in subchondral bone tissue at 6 weeks after operation., Results: The cartilage structure evaluation showed that the surface of cartilage tissue in the sham operation group was smooth and flat, and the safranin coloration was full in the full thickness of the cartilage;the cartilage tissue in the berberine group showed uneven surface layer, and the staining of safranin O was mildly decreased;the surface layer fibrosis was seen in placebo group, Safranin O faded significantly. The Mankin score in the berberine group was lower than that in placebo group( P <0.01), but higher than that in sham operation group( P <0.01). The structural evaluation of subchondral bone plate showed that the trabecular bone in sham-operated group was densely arranged;after berberine intervention, the trabeculae were closely arranged;the subchondral bone trabeculae in placebo group were relatively sparse, and the distance between trabeculae was wider. Subchondral bone plate IPP software evaluation showed that BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group( P <0.01), BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group( P <0.01), while lower than the sham operation group ( P <0.01). PCR test results showed that the expression of OPG mRNA in the berberine group was significantly higher than that in placebo group( P <0.01), and OPG mRNA in the berberine group was lower than that in sham operation group ( P <0.01). There was no significant difference in mRNA expression of RANKL among three groups( P >0.05);the ratio of OPG/RANKL in berberine group was higher than that in placebo group( P <0.01), but lower than that in sham operation group( P <0.01)., Conclusion: Intra-articular injection of berberine can effectively inhibit the resorption of subchondral bone in the early stage of OA and delay the development of the disease. The specific mechanism may be that berberine maintains the balance of OPG/RANKL system by up-regulating the expression of OPG gene in subchondral bone.

Objective: To assess the development of kissing lesions 12 months after the generation of full-thickness chondral defects., Design: Eight minipigs were randomized into 2 groups: the Φ8.5 mm full-thickness chondral defect group (8.5FT group) and the Φ6.5 mm full-thickness chondral defect group (6.5FT group). The Φ8.5 mm or Φ6.5 mm full-thickness chondral defects were prepared in the medial femoral condyle. Knee magnetic resonance imaging (MRI) was performed before sacrifice. India ink staining was performed to macroscopically assess kissing lesions. Histologic staining (hematoxylin-eosin [HE], safranin O/fast green, toluidine blue staining) and immunohistochemistry (collagen I, collagen II, collagen X, MMP-3) were performed. Microcomputed tomography analysis was completed to assess subchondral bone alterations., Results: Obvious kissing lesions were observed on the tibial plateau. Knee MRI demonstrated high cartilage signal intensity in the medial femoral condyle and opposite tibial plateau. HE staining demonstrated cartilage fibrillation and prominent cell death. The depletion of safranin O, toluidine blue staining, and collagen II was observed in the kissing lesion areas. The kissing lesion areas demonstrated increased collagen I, Collagen X, and MMP-3 expression. The 8.5FT group showed a significantly lower mean trabecular number (2.80 1/mm) than the control group (3.26 1/mm). The 6.5FT group showed a significantly increased mean trabecular thickness (0.54 mm) and a decreased mean trabecular number (2.71 1/mm) compared to the control group (0.32 mm; 3.26 1/mm)., Conclusions: Obvious kissing lesions were observed on the tibial plateau. Knee MRI demonstrated high cartilage signal The presented findings support the development of kissing lesions caused by full-thickness chondral defects.

Knee osteoarthritis (KOA) is a common and severe disease characterized by articular cartilage degeneration, subchondral bone remodeling and inflammation. The purpose of this study was to investigate the therapeutic effects of high fibular osteotomy (HFO) in a KOA rabbit model and to examine the molecular mechanisms involved in medial compartment KOA protective effects. Our data showed that HFO delayed the progression of articular cartilage damage and suppressed subchondral bone remodeling in destabilization of the medial meniscus (DMM)-induced KOA model. HFO also decreased MMP-1, MMP-3, MMP-13 and ADAMTS-5 expression, and increased Col2 and aggrecan expression. In parallel, HFO attenuated the expression of IL-1β, IL-6 and TNF-α. Furthermore, HFO suppressed DMM-mediated NFκB activation, which suggested that the molecular mechanism underlying the protective effect of HFO in medial compartment KOA may be related to the NFκB signaling pathway. Collectively, our data indicated that HFO may be a therapeutic approach to treating medial compartment KOA., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Osteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.