Hyaline Cartilage

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SFs) maintain chronic inflammation by secreting proinflammatory mediators, leading to joint destruction. While the role of proinflammatory mediators in this process is well-established, the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood. In this study, we investigated the non-inflammatory role of SFs in RA using a co-culture model, and found that SFs from RA patients promote apoptosis of human chondrocytes. Mechanistic investigations reveal that SFs can secrete small extracellular vesicles (sEVs), which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA. sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes. Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis. We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes, exacerbating cartilage damage in vivo. Moreover, chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset. This study suggests that, in RA, the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis, potentially through non-inflammatory regulation, and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.

Osteoarthritis (OA) is a degenerative joint disease associated with age, prominently marked by articular cartilage degradation. In OA cartilage, the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis. The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA. As age advances, mitochondrial function declines progressively, which leads to an imbalance in chondrocyte energy homeostasis, partially initiating the process of cartilage degeneration. Elevated oxidative stress, impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology, with mitochondrial DNA haplogroups, particularly haplogroup J, influencing OA progression. Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases, with triphenylphosphonium (TPP) emerging as the most widely utilized molecule. Other strategies encompass Dequalinium (DQA), the Szeto-Schiller (SS) tetrapeptide family, the KLA peptide, and mitochondrial-penetrating peptides (MPP), etc. These molecules share common properties of lipophilicity and positive charge. Through various technological modifications, they are conjugated to nanocarriers, enabling targeted drug delivery to mitochondria. Therapeutic interventions targeting mitochondria offer a hopeful direction for OA treatment. In the future, mitochondria-targeted therapy is anticipated to improve the well-being of life for the majority of OA patients. This review summarizes the link between chondrocyte mitochondrial dysfunction and OA, as well as discusses promising mitochondria-targeted therapies and potential therapeutic compounds.

BackgroundExternal mechanical stress plays a pivotal role in the pathogenesis of knee osteoarthritis. Piezo1 can sense mechanical stress changes on the surface of various cell types and convert them into bioelectrical signals to regulate cellular functions. Therefore, our study aimed to investigate the role of Piezo1 in mechanically induced KOA and elucidate its underlying mechanisms.MethodsIn this study, we employed various techniques to assess the effects of mechanical stress on knee joint cartilage in vivo and in vitro experiments. In vivo, we performed Micro-CT scanning, H&E staining, and ELISA analysis on the knee joints to evaluate the degree of cartilage damage and the expression of pro-inflammatory factors. In vitro, we utilized a cell stretcher to apply mechanical stress specifically to chondrocytes. Subsequently, we investigated the expression levels of Piezo1, pro-inflammatory factors, Collagen II, and other relevant markers within the chondrocytes. This approach aimed to shed light on the potential impact of Piezo1 on chondrocytes when subjected to mechanical stress.ResultsElevated expression of Piezo1 was observed in the cartilage of mice post-treadmill exercise intervention, with noticeable damage to the cartilage tissue and reduced surface smoothness. External mechanical stress significantly lowered the synthesis of the extracellular matrix in chondrocytes, potentially through the inhibition of mitochondrial autophagy levels, leading to increased mitochondrial dysfunction and the induction of pro-apoptotic proteins and pro-inflammatory cytokines.ConclusionsMechanical stress induces extracellular matrix degradation and promotes KOA progression through Piezo1-mediated chondrocyte autophagy dysfunction and apoptotic injury.

ObjectiveSingle-cell RNA-sequencing (scRNA-seq) has advanced our understanding of the heterogeneity of synovial fibroblasts and their roles in tissue repair and osteoarthritis. Here, we compared the fibroblast responses to different types and duration of joint injury in mice.DesignPublished scRNA-seq data of synovial fibroblasts from a model of joint surface injury (JSI, day 6) and two post-traumatic osteoarthritis models, destabilisation of the medial meniscus (DMM, day 7 and 2 months) and anterior cruciate ligament rupture (ACLR, day 7 and day 28), were integrated and analysed using clustering, DEG, gene-set enrichment, regulon, pseudotime trajectory and cell-cycle analyses.ResultsThe response to JSI was comparatively dominated by lining progenitor and fibroblast-like synoviocyte (FLS) expansion, while DMM and ACLR induced transient expansion of perturbed-state fibroblasts (PSF) containing a myofibroblast subset, followed by FLS expansion over time. Early injury responses were underpinned by proliferating cells that directly supplied new PSF and FLS. Molecular pathway analysis revealed rapid and sustained injury-induced transcriptomic shifts in both lining and sublining fibroblasts, with post-traumatic OA models in particular showing marked upregulation of matrix-related genes indicative of myofibroblast activity and tissue remodeling. Activity of regulons associated with the PSF response, including Hes6, Hif1α, Zfp354c, Runx1 and Foxp1, showed model and stage-dependent upregulation. Finally, co-expression of lineage-specifying transcription factors Sox9, Runx2 and Scx, indicative of multilineage potential, was a common feature of PSF in all injury models.ConclusionsThis study uncovers similarities and differences in synovial fibroblast responses between injury models, guiding future research on joint repair and osteoarthritis.