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Abstract 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. Graphical abstract

Objective: To investigate whether acupotomy could inhibit subchondral bone remodeling in knee osteoarthritis (KOA) rabbits by regulating the activity of osteoblasts and osteoclasts. Methods: KOA rabbits were prepared by immobilization for 6 and 9 weeks by Videman method. Nine groups of rabbits (control, 6 weeks and 9 weeks model, 6 weeks and 9 weeks acupotomy, 6 weeks and 9 weeks electroacupuncture, and 6 weeks and 9 weeks drug groups) received acupotomy, electroacupuncture and risedronate sodium intervention, respectively, for 3 weeks. Results: Acupotomy can inhibit the activity of osteoclasts and osteoblasts in subchondral bone by reducing the proteins expression of cathepsin K (CK) and tartrate-resistant acid phosphatase (TRAP) and decreasing the proteins expression of osteocalcin (OCN) and alkaline phosphatase (ALP), to intercept the abnormal bone resorption and bone formation of subchondral bone in 6-week and 9-week immobilization-induced KOA rabbits. Conclusion: These findings indicated that acupotomy may be more advantageous than risedronate sodium intervention in modulating subchondral bone remodeling in KOA rabbits, especially in 9-week immobilization-induced KOA rabbits.

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. [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-β in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration. Methods: The effects of BMP-4 on ECM deposition and cell proliferation were assessed in sheep NP and annulus fibrosus (AF) cells in a pellet culture model. Further, a nuclectomy induced sheep lumbar IVD degeneration model was used to evaluate the safety and effects of intradiscal BMP-4 injection on IVD regeneration. Outcomes were assessed by magnetic resonance imaging, micro-computed tomography, histological and biochemical measurements. Results: In vitro, BMP-4 significantly increased the production of proteoglycan and deposition of collagen type II and proliferation of NP and AF cells. Collagen type I deposition was not affected in NP cells, while in AF cells it was high at low BMP-4 concentrations, and decreased with increasing concentration of BMP-4. Intradiscal injection of BMP-4 induced extradiscal new bone formation and Schmorl's node-like changes in vivo. No regeneration in the NP nor AF was observed. Conclusion: Our study demonstrated that although BMP-4 showed promising regenerative effects in vitro, similar effects were not observed in a large IVD degeneration animal model. The Translational Potential of This Article: The contradictory results of using BMP-4 on IVD regeneration between in vitro and in vivo demonstrate that direct BMP-4 injection for disc degeneration-associated human chronic low back pain should not be undertaken. In addition, our results may also shed light on the mechanisms behind pathological endplate changes in human patients as a possible target for therapy.

Changes in clinical presentation, radiographic progression (RP), bone mineral density (BMD), bone turnover (BT), and cartilage turnover (CT) markers were compared in two groups of patients with hip osteoarthritis (HOA) over a period of 7 years. Each group consisted of 150 patients, including a control group on standard-of-care therapy (SC) with simple analgesics and physical exercises, and a study group (SG) on standard-of-care therapy supplemented by vitamin D3 and intravenous administration of zoledronic acid (5 mg) yearly for 3 consecutive years. Patient groups were homogenized regarding the following: (1) radiographic grade (RG), including 75 patients with hip OA RG II according to the Kellgren–Lawrence grading system (K/L), and 75 with RG III on K/L; (2) radiographic model (RM), as each of the K/L grades was subdivided into three subgroups consisting of 25 patients of different RMs: atrophic ('A'), intermediate ('I'), and hypertrophic ('H'); (3) gender-equal ratio of men and women in each subgroup (Female/Male = 15/10). The following parameters were assessed: (1) clinical parameters (CP), pain at walking (WP-VAS 100 mm), functional ability (WOMAC-C), and time to total hip replacement (tTHR); (2) radiographic indicators(RI)—joint space width (JSW) and speed of joint space narrowing (JSN), changes in BMD (DXA), including proximal femur (PF-BMD), lumbar spine (LS-BMD), and total body (TB-BMD); (3) laboratory parameters (LP)—vitamin D3 levels and levels of BT/CT markers. RV were assessed every 12 months, whereas CV/LV were assessed every 6 months. Results: Cross-sectional analysis (CsA) at baseline showed statistically significant differences (SSD) at p < 0.05 in CP (WP, WOMAC-C); BMD of all sites and levels of CT/BT markers between the 'A' and 'H' RM groups in all patients. Longitudinal analysis (LtA) showed SSD (p < 0.05) between CG and SG in all CP (WP, WOMAC-C, tTHR) parameters of RP (mJSW, JSN), BMD of all sites, and levels of CT/BT markers for all 'A' models and in 30% of 'I'-RMs (those with elevated markers for BT/CT at baseline and during the observation period). Conclusion: The presence of SSD at baseline ('A' vs. 'H') supported the thesis that at least two different subgroups of HOA exist: one associated with 'A' and the other with 'H' models. D3 supplementation and the intravenous administration of bisphosphonate were the treatment strategies that slowed down RP and postponed tTHR by over 12 months in the 'A' and 'I' RM with elevated BT/CT markers. [ABSTRACT FROM AUTHOR]

There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.

Objective: Our study was performed to investigate whether micro-223 promotes diabetic Osteoarthritis (OA) progression by regulating cartilage degeneration and subchondral bone remodeling., Methods: The expression of miR-223 in human normal cartilage, OA cartilage, and subchondral bone tissue with or without DM was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). miR-223 mimic or inhibitor was transfected into chondrocytes. Cell viability and apoptosis were assessed by 3-(4,5)-dimethylthiahiazo(-2)-3,5-diphenyltetrazolium bromide (MTT) and Terminal Deoxynucleotidyl Transferase(TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively., Results: miR-223 was significantly higher in human diabetic OA cartilage and subchondral bone compared with normal OA and healthy control. Overexpression of miR-223 accelerated cartilage degeneration and subchondral bone sclerosis in diabetic OA mice, whereas miR-223 inhibition had the opposite effect. In vitro upregulation of miR-223 decreased proliferation and enhanced apoptosis of chondrocytes. Meanwhile, downregulation of miR-223 promoted glycosaminoglycan (GAG) production in chondrocytes., Conclusion: miR-223 promotes diabetic OA progression by regulating cartilage degeneration and subchondral bone remodeling both in vitro and in vivo ., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Animal models are frequently used to study post-traumatic osteoarthritis (PTOA). A common anterior cruciate ligament (ACL) injury model is surgical transection, which may introduce confounding factors from surgery. Noninvasive models could model human injury more closely. The purpose of this study was to compare subchondral and epiphyseal trabecular bone remodeling after surgical transection and noninvasive rupture of the ACL. Methods: Thirty-six rats were randomized to an uninjured control, surgical transection (Transection), or noninvasive rupture (Rupture). Animals were randomized to 4 or 10 week time points (n = 6 per group). Micro computed tomography (μCT) imaging was performed with an isotropic voxel size of 12 μm. Subchondral and epiphyseal bone was segmented semi-automatically, and morphometric analysis was performed. Results: Transection caused a greater decrease in subchondral bone volume fraction (BV/TV) than Rupture in the femur and tibia. Rupture had greater subchondral bone tissue mineral density (TMD) at 4 and 10 weeks in the femur and tibia. Subchondral bone thickness (SCB.Th) was decreased in the femur in Transection only. Epiphyseal BV/TV was decreased in Transection only, and Rupture exhibited increased femoral epiphyseal TMD compared to both Control and Transection. Rupture exhibited greater femoral epiphyseal trabecular thickness (Tb.Th.) compared to Control and Transection at 4 weeks, and both Rupture and Transection had increased femoral epiphyseal Tb.Th. at 10 weeks. Epiphyseal trabecular number (Tb.N) was decreased in both injury groups at both time points. Femoral and tibial epiphyseal structure model index (SMI) increased in both groups. Conclusions: The two injury models cause differences in post-injury bone morphometry, and surgical transection may be introducing confounding factors that affect downstream bony remodeling. [ABSTRACT FROM AUTHOR]

• A pH-responsive bisphosphonate-conjugated nano-apatite system was prepared. • This system effectively suppressed osteoclast activity in subchondral bone. • This system inhibited the intrusion of subchondral bone into cartilage. • Cartilage degeneration was attenuated by the NP-BP system. Osteoarthritis (OA) has become one of the most prevalent and costly diseases worldwide. Previous studies have confirmed that subchondral bone abnormal remodeling caused by overactive osteoclast bone resorption was the major cause of OA. In this study, we fabricated a bisphosphonate-conjugated nano-apatite (NP-BP) system via hydrothermal method and in-situ adsorption process. The NP-BP showed sustainable and pH-responsive release behavior of bisphosphonate. The in vitro experiment revealed that NP-BP could effectively inhibit osteoclast differentiation and suppress osteoclast bone resorption through down regulating the expressions of osteoclastic related genes, including TRAP, OSCAR, NFATc1, and Cathepsin K. The in vivo study in an OA rat model indicated that the NP-BP could relieve joint pain, attenuate articular cartilage degeneration, and lower histologic OARSI score. In parallel, the micro-CT analysis, including total tissue volume (TV), subchondral bone plate thickness (SBP Th.), and trabecular pattern factor (Tb. Pf), showed that the NP-BP could efficiently inhibit subchondral bone abnormal remodeling. In addition, the immunostaining analyses and the micro-CT based angiography demonstrated that the NP-BP suppressed the expressions of Collagen X, RANKL, Osterix, and CD31 and inhibited aberrant angiogenesis. Moreover, the NP-BP inhibited the intrusion of subchondral bone into calcified cartilage. As a result, the developed pH-responsive NP-BP system, which showed high efficiency in inhibiting osteoclastic bone resorption and subchondral bone abnormal remodeling, has potential applications for early OA treatment. [ABSTRACT FROM AUTHOR]

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.

Temporomandibular joint (TMJ) inflammation is a potential risk factor of osteoarthritis (OA) but the detailed degenerative changes in the inflamed TMJ remain unclear. In this study, we evaluated the changes of condylar cartilage and subchondral bone in rat inflamed TMJ induced by Freund's complete adjuvant (CFA). Articular cavity was injected with CFA and the TMJ samples were collected 1, 2, 3, and 4-week post-injection. Hematoxylin & Eosin (H&E) staining, toluidine blue (TB) staining, Safranin O (S.O) staining, Masson trichrome staining and micro-CT were used to assess TMJ degeneration during inflammation. Osteoclast and osteoblast activities were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and osteocalcin (OCN) immunohistochemistry staining respectively. The expression of receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) in condylar cartilage and subchondral bone was also evaluated through immunohistochemistry and RANKL/OPG ratio was evaluated. Reduced cartilage thickness, decreased number of chondrocytes, and down-regulated proteoglycan expression were observed in the condylar cartilage in the inflamed TMJ. Enhanced osteoclast activity, and expanded bone marrow cavity were reached the peak in the 2-week after CFA-injection. Meanwhile the RANKL/OPG ratio in the cartilage and subchondral bone also increased in the 2-week CFA-injection. Immature, unmineralized new bones with irregular trabecular bone structure, atypical condylar shape, up-regulated OCN expression, and decreased bone mineral density (BMD) were found in the inflamed TMJ. The time-dependent degeneration manner of TMJ cartilage and subchondral bone was found in CFA-induced arthritis rat model. The degeneration in the TMJ with inflammation might be a risk factor and should be concerned.