Chronic monoarticular joint pain in paediatric patients is prevalent, yet the aetiology often remains unidentified when initial imaging yields no abnormalities. This case highlights a rare but significant differential diagnosis: synovial chondromatosis. Early identification is essential to prevent joint damage, but diagnosis is frequently delayed due to subtle clinical manifestations and inconclusive initial imaging. Notably, mechanical symptoms and recurrent joint effusions are key indicators. In such cases, persistent pain with recurrent effusion should prompt early consideration of synovial pathology even when initial radiographs are unremarkable. Repeat imaging may be valuable in demonstrating interval development of ossified loose bodies; however, this case suggests that the underlying disease can be present well before calcification becomes radiographically visible. Therefore, clinical persistence and mechanical symptoms should drive timely escalation of evaluation. When concern remains, earlier use of targeted synovial assessment and advanced imaging should be considered.

Osteoporotic bone defects (OBD) present a major clinical challenge, largely due to a pathological bone microenvironment that severely compromises regenerative capacity. Moving beyond conventional classification schemes that often fail to capture this pathological complexity, our review establishes a conceptual framework that categorizes emerging biomaterials by mirroring the intrinsic functional components of the bone microenvironment itself—namely, ion-releasing, metabolite-based, extracellular matrix (ECM)-mimetic, and cytokine-loaded systems. The component-centric taxonomy not only systematizes a disparate field but also directly links material design to underlying pathological mechanisms. Accordingly, these materials are engineered not merely as structural replacements but as active modulators designed to reprogram the pathological niche by concurrently targeting key mechanisms such as cellular dysfunction and immune-metabolic dysregulation. Furthermore, we explore the emerging roles of bone organoids and artificial intelligence (AI) in refining preclinical models. By integrating a deep biological understanding of the niche with engineering innovation, our work aims to provide a cohesive framework and forward-looking perspective to guide the development of effective, microenvironment-targeted regenerative strategies.

The immunological hallmarks associated with ankylosing spondylitis (AS) occurrence and development were unclear. After recruiting healthy donors and patients in different stages, we performed single-cell RNA sequencing for peripheral blood mononuclear cells (PBMCs) and relied on T-cell receptor (TCR) and B-cell receptor (BCR) analyses to explore the immunological patterns causing AS onset and different outcomes. Effector T/B cells possessed marked clonal expansion and AS lesions were characterized by B-cell clonal expansion. However, patients in remission showed weak T/B-cell clonal expansion. The usage of top 10 CDR3 sequences and the rearrangement of V(D)J genes in AS remission was less diverse. BCR-V(D)J rearrangement in healthy donors was more specific. AS different stages all exhibited preferred TRA genes (TRAV17 for onset, TRAV9-2 for aggravation, and TRAV23/DV6 and TRAJ56 for remission) and TRBV12-5 was overrepresented in remission. The top two paired TCR-V/J genes for AS different stages were all different (TRBV20-1/TRBJ2-1 and TRAV14/DV4/TRAJ53 for onset, TRBV7-9/TRBJ2-5 and TRBV20-1/TRBJ2-3 for aggravation, and TRBV27/TRBJ2-1 and TRBV28/TRBJ2-1 for remission). IGHV3-30 and IGHV4-30–2 were overrepresented in remission and the top two paired BCR-V/J genes for AS different stages were also different (IGHV3-23/IGHJ4 and IGHV3-7/IGHJ3 for onset, IGLV1-44/IGLJ2 and IGHV3-7/IGHJ4 for aggravation, and IGHV3-74/IGHJ4 and IGLV3-1/IGLJ2 for remission). These findings provide insights into the dynamic immune-response features of AS onset and outcomes, suggesting that there is an important connection between driving AS lesions and B-cell clonal expansion, and decreased V(D)J usage diversity in remission has guiding value for inducing rapid remission in AS patients.

BACKGROUND:GPR35, a member of the G protein-coupled receptor (GPCR) family, promotes osteogenic differentiation and ameliorates inflammation when its expression is enhanced. However, its role in bone homeostasis under hyperuricemia (HUA) conditions remains unexplored, and effective clinical agents for managing osteoporosis comorbid with HUA are scarce. This study aimed to investigate the osteoprotective potential of the GPR35 agonist isobavachin (IBC) against HUA-induced bone loss, focusing on its mechanism involving NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome modulation. METHODS:Bone tissue markers of bone homeostasis and inflammatory infiltration were evaluated in patients with hyperuricemia. To delineate the relationship of HUA, bone homeostasis, and GPR35, osteoblasts (OB) and osteoclasts (OC) were treated with high concentrations of soluble uric acid, in conjunction with label-free cellular assays. The mechanisms underlying the effects of the GPR35 agonist IBC were investigated using molecular docking, in vitro cell culture with IBC treatment, and siRNA-mediated gene silencing. Furthermore, hyperuricemic model mice were established in C57BL/6 J mice to corroborate the bone loss induced by HUA and evaluate the osteoprotective efficacy of IBC. RESULTS:Analysis of bone tissue from HUA patients revealed increased activity of both OB and OC, along with inflammatory cell infiltration. Consistently, in vitro experiments demonstrated that exposure to high concentrations of soluble uric acid specifically and significantly impaired OB differentiation and mineralization. This inhibitory effect was closely associated with NLRP3 inflammasome activation. Furthermore, high concentrations of soluble uric acid treatment modulated GPR35 expression levels in cultured cells. Critically, the GPR35 agonist IBC activated GPR35 and promoted osteogenic effects. Mechanistically, GPR35 knockdown experiments confirmed that IBC exerted its bone-promoting actions primarily via the GPR35-NLRP3 signaling axis. Importantly, these findings were corroborated in a chronic hyperuricemia mouse model, where IBC treatment effectively attenuated HUA-induced bone loss compared to the standard antihyperuricemic agent allopurinol. CONCLUSIONS:Our findings demonstrate that GPR35 activation protects OB from HUA-induced bone loss. The GPR35 agonist IBC enhances osteogenic differentiation by modulating the GPR35-NLRP3 signaling axis, effectively attenuating bone loss in HUA. These results identify IBC as a promising novel therapeutic candidate for managing HUA-associated osteoporosis.

Rheumatoid arthritis (RA) is an inflammatory disease that progresses from synovial inflammation to cartilage and bone destruction. Eliminating pro-inflammatory M1 macrophages is a promising strategy for RA treatment, but is impeded by cytoprotective autophagy. Herein, we report an effective autophagy blockage-promoted apoptosis/ferroptosis strategy using multifunctional ferric phosphate-decorated, methotrexate-loaded polypyrrole nanoparticles (PPy-FePi-MTX NPs) to achieve enhanced RA treatment effects. When injected into the knee joints of a collagen-induced DBA/1J mouse model of RA, the payloads on PPy NPs are released under the stimulation of an inflammatory microenvironment. The released MTX can directly induce M1 macrophage apoptosis. Upon near-infrared laser irradiation, the photothermal effect of PPy NPs further promotes cellular apoptosis. In addition, Fe3+ reacts with intracellular over-expressed glutathione to form Fe2+, which can convert hydrogen peroxide into toxic hydroxyl radicals. This redox process could deplete glutathione, inactivate glutathione peroxidase 4, and cause lipid peroxidation accumulation, resulting in ferroptosis of inflammatory M1 macrophages. Furthermore, PO43- disrupts the normal function of lysosomes by pH disturbance, disabling the cytoprotective autophagy of M1 macrophages for enhanced anti-RA effects. This work develops multifunctional PPy NPs for RA treatment through effective elimination of pro-inflammatory M1 macrophage.

Biphasic calcium phosphate (BCP) composites are widely employed for bone repair, with osteogenic performance governed by both the HA:β-TCP ratio and crystallinity. While compositional tuning has been extensively investigated, the role of crystallinity as a multiscale regulator of composite properties remains insufficiently explored. Here, BCP composites with controlled crystallinity were fabricated by adjusting calcination temperature, and systematically characterized across multiple length scales. Reducing crystallinity decreased calcium ion release but enhanced surface roughness, hydrophilicity, and protein adsorption, while maintaining mechanical competence sufficient for load-bearing environments. These physicochemical changes synergistically promoted cytoskeletal extension, integrin-mediated signaling, and osteogenic gene expression in bone marrow stromal cells. Among the tested BCP composites, BCP2, with moderately low crystallinity, showed the best osteogenic outcomes both in vitro and in vivo, due to its balanced combination of favorable surface properties and moderate ion release. In contrast, BCP1, with the lowest crystallinity and superior surface properties, exhibited slightly lower osteogenesis than BCP2, likely due to insufficient calcium release. BCP3, although highly crystalline with abundant calcium release, showed the lowest osteogenic performance, possibly due to insufficient stimulation of surface characteristics during cell-material interactions in vitro and in vivo. Transcriptomic profiling further confirmed that BCP2 activated integrin-mediated cytoskeletal pathways to drive osteogenesis. Overall, this study identifies crystallinity as a key tunable design parameter that indirectly regulates osteogenesis through its coupled effects on surface and ionic cues, providing strategic insights for the rational development of BCP composites for bone regeneration.

Mechanical overload is a critical contributor to cartilage degeneration in osteoarthritis (OA) pathogenesis. Circular RNA (circRNA) is expected to provide a long-lasting therapy for OA. However, the involvement of the circRNA-associated competitive endogenous RNA network in chondrocyte senescence induced by mechanical overloading remains unestablished. A mechanical overloading-induced chondrocyte senescence model in human primary chondrocytes is constructed, and differences in the expression of circRNAs and miRNAs were analyzed. The biological roles of circKIAA0586/miR-335-5p in chondrocyte senescence and OA progression under mechanical overloading and its downstream targets were determined using gain- and loss-of-function experiments in various biochemical assays in human chondrocytes. The in vivo effects of circKIAA0586 overexpression were also determined in destabilization of the medial meniscus (DMM) OA mice and aged spontaneous OA mice. The mechanical overloading-induced chondrocyte senescence was aggravated by miR-335-5p or circKIAA0586 knockdown. Accumulated DNA damage response was observed following mechanical overloading, which reduced after miR-335-5p inhibition or circKIAA0586 supplementation. MiR-335-5p was regulated by circKIA0586 adsorption. HELLS was prominently down-regulated following mechanical overloading treatment. Moreover, miR-335-5p bound to lymphoid-specific helicase (HELLS) mRNA during mechanical overloading was demonstrated to mediate the nonhomologous end joining (NHEJ) pathway, thereby inducing DNA damage and senescence. In addition, the senescence delaying and cartilage protective functions of circKIAA0586 and HELLS were validated in DMM OA mice and aged spontaneous OA mice. Our findings suggest that miR-335-5p, which escapes circKIAA0586 adsorption, facilitates mechanical overloading-induced chondrocyte senescence and OA progression by impairing the NHEJ pathway through HELLS inhibition. Overall, targeting circKIAA0586/miR-335-5p/HELLS signaling provides a novel therapeutic approach for OA.

A detrimental feedback loop between hypoxia and oxidative stress consistently drives macrophage polarization toward a pro-inflammatory M1 phenotype, thus persistently aggravating rheumatoid arthritis (RA) progression. Herein, an enzyme-catalyzed nanoplatform with synergistic hypoxia-relieving and reactive oxygen species (ROS)-scavenging properties was developed using bovine serum albumin-bilirubin-platinum nanoparticles (BSA-BR-Pt NPs). Bilirubin was employed to eliminate ROS, while platinum exhibited a synergistic effect in scavenging ROS and simultaneously generated oxygen. In mice RA model, BSA-BR-Pt NPs treatment exhibited superior effects, resulting in significant improvements in joint inflammation, cartilage damage, and bone erosion, compared to methotrexate, the most widely used antirheumatic drug. Mechanistically, RNA-sequencing data and experimental results elucidated that BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages via switching glycolysis to oxidative phosphorylation through the inhibition of HIF-1α pathway. Collectively, this research for the first time elaborated the underlying mechanism of enzyme-catalyzed nanoplatform in orchestrating macrophage polarization, and identified a novel therapeutic strategy for RA and other inflammatory disorders.

Fibrotic ligament diseases (FLDs) are diseases caused by the pathological accumulation of periarticular fibrotic tissue, leading to functional disability around joint and poor life quality. Relaxin (RLX) has been reported to be involved in the development of fibrotic lung and liver diseases. Previous studies have shown that RLX can block pro-fibrotic process by reducing the excess extracellular matrix (ECM) formation and accelerating collagen degradation in vitro and in vivo. Recent studies have shown that RLX can attenuate connective tissue fibrosis by suppressing TGF-β/Smads signaling pathways to inhibit the activation of myofibroblasts. However, the specific roles and mechanisms of RLX in FLDs remain unclear. Therefore, in this review, we confirmed the protective effect of RLX in FLDs and summarized its mechanism including cells, key cytokines and signaling pathways involved. In this article, we outline the potential therapeutic role of RLX and look forward to the application of RLX in the clinical translation of FLDs.

The repair of bone defects resulting from high-energy trauma, infection, or pathological fracture remains a challenge in the field of medicine. The development of biomaterials involved in the metabolic regulation provides a promising solution to this problem and has emerged as a prominent research area in regenerative engineering. While recent research on cell metabolism has advanced our knowledge of metabolic regulation in bone regeneration, the extent to which materials affect intracellular metabolic remains unclear. This review provides a detailed discussion of the mechanisms of bone regeneration, an overview of metabolic regulation in bone regeneration in osteoblasts and biomaterials involved in the metabolic regulation for bone regeneration. Furthermore, it introduces how materials, such as promoting favorable physicochemical characteristics (e.g., bioactivity, appropriate porosity, and superior mechanical properties), incorporating external stimuli (e.g., photothermal, electrical, and magnetic stimulation), and delivering metabolic regulators (e.g., metal ions, bioactive molecules like drugs and peptides, and regulatory metabolites such as alpha ketoglutarate), can affect cell metabolism and lead to changes of cell state. Considering the growing interests in cell metabolic regulation, advanced materials have the potential to help a larger population in overcoming bone defects.

Background The aggressive phenotype of fibroblast-like synoviocytes (FLS) has been identified as a contributing factor to the exacerbation of rheumatoid arthritis (RA) through the promotion of synovitis and cartilage damage. Regrettably, there is currently no effective therapeutic intervention available to address this issue. Recent research has shed light on the crucial regulatory role of R-spondin-2 (Rspo2) in cellular proliferation, cartilage degradation, and tumorigenesis. However, the specific impact of Rspo2 on RA remains poorly understood. We aim to investigate the function and mechanism of Rspo2 in regulating the aggressive phenotype of FLS and maintaining chondrocyte homeostasis in the context of RA. Methods The expression of Rspo2 in knee joint synovium and cartilage were detected in RA mice with antigen-induced arthritis (AIA) and RA patients. Recombinant mouse Rspo2 (rmRspo2), Rspo2 neutralizing antibody (Rspo2-NAb), and recombinant mouse DKK1 (rmDKK1, a potent inhibitor of Wnt signaling pathway) were used to explore the role and mechanism of Rspo2 in the progression of RA, specifically in relation to the aggressive phenotype of FLS and chondrocyte homeostasis, both in vivo and in vitro. Results We indicated that Rspo2 expression was upregulated both in synovium and articular cartilage as RA progressed in RA mice and RA patients. Increased Rspo2 upregulated the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), as the ligand for Rspo2, and β-catenin in FLS and chondrocytes. Subsequent investigations revealed that intra-articular administration of rmRspo2 caused striking progressive synovitis and articular cartilage destruction to exacerbate RA progress in mice. Conversely, neutralization of Rspo2 or inhibition of the Wnt/β-catenin pathway effectively alleviated experimental RA development. Moreover, Rspo2 facilitated FLS aggressive phenotype and disrupted chondrocyte homeostasis primarily through activating Wnt/β-catenin pathway, which were effectively alleviated by Rspo2-NAb or rmDKK1. Conclusions Our data confirmed a critical role of Rspo2 in enhancing the aggressive phenotype of FLS and disrupting chondrocyte homeostasis through the Wnt/β-catenin pathway in the context of RA. Furthermore, the results indicated that intra-articular administration of Rspo2 neutralizing antibody or recombinant DKK1 might represent a promising therapeutic strategy for the treatment of RA.

Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis（RA）. Fatty acid-binding protein 4（FABP4）, a novel adipokine that regulates inflammation and angiogenesis, has been extensively studied in a variety of organs and diseases. However, the effect of FABP4 on RA remains unclear. Here, we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA. The increase in FABP4 promoted synovitis, angiogenesis, and cartilage degradation to exacerbate RA progression in vivo and in vitro, whereas BMS309403（a FABP4 inhibitor） and anagliptin（dipeptidyl peptidase 4inhibitor） inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression. Further studies showed that constitutive activation of mammalian target of rapamycin complex 1（m TORC1） by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice. In contrast, inhibition of m TORC1 by ras homolog enriched in brain（Rheb1） disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice. Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis, angiogenesis, and cartilage degradation in RA. BMS309403 and anagliptin inhibited FABP4expression in synovial M1-polarized macrophages to alleviate RA development. Hence, FABP4 may represent a potential target for RA therapy.

背景:骨关节炎以关节软骨的退变为主要病理特征,作为软骨中唯一的细胞,软骨细胞的衰老是骨关节炎发病的重要机制之一.但是骨关节炎的具体发病机制目前仍未清楚,因此探索疾病过程中的分子机制和信号通路变化,希望为骨关节炎的诊断与治疗提供新的生物靶点和研究方向.目的:探讨在骨关节炎进程中软骨PDZ结构域蛋白1(PDZ Domain Containing 1,PDZK1)对软骨细胞衰老的影响.方法:①8周龄C57/BL6小鼠随机分为实验组和假手术组,实验组又随机分为4,8周2个亚组.实验组小鼠行右侧膝关节内侧半月板胫骨韧带切除,游离内侧半月板,诱导骨关节炎;假手术组小鼠则仅切开关节囊而不行内侧韧带切除和半月板游离,检测PDZK1表达量.②用Ⅱ型胶原酶消化法分离新生C57/BL6乳鼠软骨细胞并培养,用10μg/L白细胞介素1β构建骨关节炎体外细胞模型,并利用siRNA-PDZK1敲低PDZK1,共分为未处理组、白细胞介素1β处理组(白细胞介素1β组)、siRNA-PDZK1组(si-PD组)、白细胞介素1β与siRNA-PDZK1共同刺激组(si-PD+白细胞介素1β组).检测软骨细胞PDZK1表达量;检测软骨细胞形成指标(如Ⅱ型胶原a1)、分解代谢指标(如基质金属蛋白酶13)以及软骨细胞衰老指标(如P16、P21、P53).结果 与结论:①在C57/BL6骨关节炎小鼠膝关节软骨中,PDZK1表达较假手术组明显减少;②在C57/BL6乳鼠的原代软骨细胞中,通过免疫印迹实验证实,白细胞介素1β组与si-PD组的PDZK1表达量相比未处理组明显下降;si-PD组软骨细胞合成代谢指标Ⅱ型胶原a1表达量相比未处理组显著降低;si-PD+白细胞介素1β组分解代谢指标基质金属蛋白酶13表达量较白细胞介素1β组显著增加;③利用C57/BL6乳鼠的原代软骨细胞,通过实时荧光定量PCR证明,si-PD组敲低PDZK1后,细胞衰老指标P16、P21、P53表达较未处理组显著增加;④提示在骨关节炎进展中,软骨细胞中PDZK1的表达是降低的;PDZK1缺失可促进软骨细胞衰老,加重骨关节炎.所以PDZK1可能是骨关节炎发病过程中调节软骨细胞衰老的重要基因;对于PDZK1缺失促进软骨细胞衰老的机制,还需要更深入的研究.

Osteopontin (OPN) has been proved to be closely related to the pathogenesis of osteoarthritis (OA), but the role of OPN in the pathogenesis of OA has not been fully clarified. Current studies on OPN in OA mostly focus on articular cartilage, synovial membrane and articular fluid, while ignoring its role in OA subchondral bone turnover and remodeling. In this study, we used a destabilization OA mouse model to investigate the role of OPN in OA subchondral bone changes. Our results indicate that increased expression of OPN accelerates the turnover and remodeling of OA subchondral bone, promotes the formation of h-type vessels in subchondral bone, and mediates articular cartilage degeneration induced by subchondral bone metabolism. In addition, our results confirmed that inhibition of PI3K/AKT signaling pathway inhibits OPN-mediated OA subchondral bone remodeling and cartilage degeneration. This study revealed the role and mechanism of OPN in OA subchondral bone, which is of great significance for exploring specific biological indicators for early diagnosis of OA and monitoring disease progression, as well as for developing drugs to regulate the metabolism and turnover of subchondral bone and alleviate the subchondral bone sclerosis of OA.

Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-κB signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.