Lubricin, secreted primarily by chondrocytes, plays a critical role in maintaining the function of the cartilage lubrication system. However, both external factors such as friction and internal factors like oxidative stress can disrupt this system, leading to osteoarthritis. Inspired by lubricin, a lubricating nanozyme, that is, Poly-2-acrylamide-2-methylpropanesulfonic acid sodium salt-grafted aminofullerene, is developed to restore the cartilage lubrication system using an \"In-Out\" strategy. The \"Out\" aspect involves reducing friction through a combination of hydration lubrication and ball-bearing lubrication. Simultaneously, the \"In\" aspect aims to mitigate oxidative stress by reducing free radical, increasing autophagy, and improving the mitochondrial respiratory chain. This results in reduced chondrocyte senescence and increased lubricin production, enhancing the natural lubrication ability of cartilage. Transcriptome sequencing and Western blot results demonstrate that it enhances the functionality of mitochondrial respiratory chain complexes I, III, and V, thereby improving mitochondrial function in chondrocytes. In vitro and in vivo experiments show that the lubricating nanozymes reduce cartilage wear, improve chondrocyte senescence, and mitigate oxidative stress damage, thereby mitigating the progression of osteoarthritis. These findings provide novel insights into treating diseases associated with oxidative stress and frictional damage, such as osteoarthritis, and set the stage for future research and development of therapeutic interventions.

Sarcopenia, a geriatric syndrome characterized by progressive loss of muscle mass and strength, and osteoarthritis, a common degenerative joint disease, are both prevalent in elderly individuals. However, the relationship and molecular mechanisms underlying these two diseases have not been fully elucidated. In this study, we screened microarray data from the Gene Expression Omnibus to identify associations between sarcopenia and osteoarthritis. We employed multiple statistical methods and bioinformatics tools to analyze the shared DEGs (differentially expressed genes). Additionally, we identified 8 hub genes through functional enrichment analysis, protein-protein interaction analysis, transcription factor-gene interaction network analysis, and TF-miRNA coregulatory network analysis. We also discovered potential shared pathways between the two diseases, such as transcriptional misregulation in cancer, the FOXO signalling pathway, and endometrial cancer. Furthermore, based on common DEGs, we found that strophanthidin may be an optimal drug for treating sarcopenia and osteoarthritis, as indicated by the Drug Signatures database. Immune infiltration analysis was also performed on the sarcopenia and osteoarthritis datasets. Finally, receiver operating characteristic (ROC) curves were plotted to verify the reliability of our results. Our findings provide a theoretical foundation for future research on the potential common pathogenesis and molecular mechanisms of sarcopenia and osteoarthritis.

Osteoarthritis (OA) is a prevalent condition in horses, leading to changes in trabecular bone structure and radiographic texture. Although fractal dimension (FD) and lacunarity have been applied to quantify these changes in humans, their application in horses remains nascent. This study evaluated the use of FD, bone area fraction (BA/TA), and lacunarity in quantifying trabecular bone differences in the proximal phalanx (P1) in 50 radiographic examinations of equine metacarpophalangeal joints with varying OA degrees. In the dorsopalmar view, regions of interest were defined in the trabecular bone of the proximal epiphysis, medial and lateral to the sagittal groove of P1. Lower BA/TA values were observed medially in horses with severe OA (P=0.003). No significant differences in FD and lacunarity were found across OA degrees (P>0.1). FD, BA/TA, and lacunarity were not effective in identifying radiographic texture changes in the P1 trabecular bone in horses with different metacarpophalangeal OA degrees.

OBJECTIVE: The aim of this consensus was to develop evidence- and expert-based patient-focused recommendations on the appropriateness of intra-articular platelet-rich plasma (PRP) injections in different clinical scenarios of patients with knee osteoarthritis (OA).
METHODS: The RAND/UCLA Appropriateness Method was used by the European Society of Sports Traumatology, Knee Surgery, and Arthroscopy (ESSKA), as well as the International Cartilage Regeneration and Joint Preservation Society (ICRS) to reach a consensus and produce recommendations for specific patient categories combining best available scientific evidence with the collective judgement of a panel of experts.
RESULTS: Scenarios were defined based on first treatment vs first injective treatment vs second injective treatment, age (<50/50-65/66-80/>80), tibiofemoral vs patellofemoral involvement, OA level (Kellgren-Lawrence/KL 0-I/II-III/IV), and joint effusion (dry knee, minor-mild or major effusion). Out of 216 scenarios, in 84 (38.9%) the indication was considered appropriate, in 9 (4.2%) inappropriate and in 123 (56.9%) uncertain. The parameters associated with the highest consensus were PRP use after failed injective treatments (62.5%), followed by PRP after failed conservative treatments and KL 0-III scenarios (58.3%), while the highest uncertainty was found for PRP use as first treatment and KL IV OA (91.7% and 87.5% of uncertain scenarios, respectively).
CONCLUSIONS: This ESSKA-ICRS consensus established recommendations on the appropriateness or inappropriateness of PRP injections for the treatment of knee OA, providing a useful reference for clinical practice. PRP injections are considered appropriate in patients aged ≤80 years with knee KL 0-III OA grade after failed conservative non-injective or injective treatments, while they are not considered appropriate as first treatment nor in KL IV OA grade.
METHODS: Level I.

The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence has shown that OA is a heterogeneous disease with multiple phenotypes, and it is unlikely to respond to one-size-fits-all treatments. Inflammation is recognized as an important phenotype of OA and is associated with worse pain and joint deterioration. Therefore, it is believed that anti-inflammatory treatments may be more effective for OA with an inflammatory phenotype. In this review, we summarized clinical trials that evaluated anti-inflammatory treatments for OA and discussed whether these treatments are more effective in inflammatory OA phenotypes compared to general OA patients.

OBJECTIVE: To evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee OA.
METHODS: This was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a WOMAC pain score ≥20 out of 50 at screening and baseline visits. Subjects having any other knee condition were excluded. Use of analgesics was prohibited, except for rescue medication. The primary endpoint was change from baseline (CFB) in WOMAC pain at Week 8. Secondary endpoints were CFB in WOMAC function and total, ICOAP, PGA, and 20-meter walk test. Exploratory endpoints included structural CFB in MRI entities.
RESULTS: 288 subjects were randomized to SB-061 (n=145) or placebo (n=143), and 252 (87.5%) completed injections. The groups were comparable at baseline. The primary endpoint was not met, as no significant difference in the CFB of the WOMAC pain score at Week 8 between groups was observed, nor at any other time point during the study. Similarly, neither of the secondary or exploratory endpoints indicated any significant difference between groups. The frequency and type of adverse events was similar between groups. SB-061 was well-tolerated.
CONCLUSIONS: Intra-articular injections of SB-061 administered at baseline, Wk 16, and Wk 32, over one year in subjects with knee OA was safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo.
UNASSIGNED: 2019-004515-31.

The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad \"mechanome\" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.

OBJECTIVE: To identify multimorbidity trajectories over 20 years among incident osteoarthritis (OA) individuals and OA-free matched references.
METHODS: Cohort study using prospectively collected healthcare data from the Skåne region, Sweden (~1.4 million residents). We extracted diagnoses for OA and 67 common chronic conditions. We included individuals aged 40+ years on 31 December 2007, with incident OA between 2008 and 2009. We selected references without OA, matched on birth year, sex, and year of death or moving outside the region. We employed group-based trajectory modelling to capture morbidity count trajectories from 1998 to 2019. Individuals without any comorbidity were included as a reference group but were not included in the model.
RESULTS: We identified 9846 OA cases (mean age: 65.9 (SD 11.7), female: 58%) and 9846 matched references. Among both cases and references, 1296 individuals did not develop chronic conditions (no-chronic-condition class). We identified four classes. At the study outset, all classes exhibited a low average number of chronic conditions (≤1). Class 1 had the slowest progression towards multimorbidity, which increased progressively in each class. Class 1 had the lowest count of chronic conditions at the end of the follow-up (mean: 2.9 (SD 1.7)), while class 4 had the highest (9.6 (2.6)). The presence of OA was associated with a 1.29 (1.12, 1.48) adjusted relative risk of belonging to class 1 up to 2.45 (2.12, 2.83) for class 4.
CONCLUSIONS: Our findings suggest that individuals with OA face an almost threefold higher risk of developing severe multimorbidity.

BACKGROUND: Osteoarthritis (OA) is a progressive condition affecting the joints that lacking effective therapy. However, the underlying molecular mechanism has not been fully clarified.
METHODS: A model of OA was established in Sprague-Dawley (SD) rats through intra-articularly injected with monoiodoacetate (MIA). Western blot analysis was used to identify the levels of UBE2I and hnRNPA2B1 in articular cartilage. Overexpression and siRNA vectors for UBE2I were constructed and transfected into rat chondrocytes. CCK-8, TUNEL and transwell assay were utilized to assess the cell viability, apoptosis and migration ability. Western blot analysis was used to determine the levels of chondrogenic-specific genes including SOX9, COL2A1, Aggrecan, and PRG4. Then, molecular interactions were confirmed by immunoprecipitation.
RESULTS: We observed significant upregulation of UBE2I and hnRNPA2B1 expression in articular cartilage samples of OA. The Pearson correlation analysis revealed positive correlation between UBE2I and hnRNPA2B1 levels. Functional experiments showed that increased UBE2I expression significantly suppressed cell growth, migration, and reduced the expression of chondrogenic-specific genes, while decreasing UBE2I levels had the opposite effects. Molecular interactions between UBE2I and hnRNPA2B1were determined via co-localization and immunoprecipitation. SUMO1 and SUMO3 proteins were enriched by immunoprecipitation using hnRNPA2B1 antibodies. Rescue experiments were performed using SUMOylation inhibitor (2-D08) and SUMOylation activator (N106). Overexpression of UBE2I increased the expression of hnRNPA2B1 in the cytoplasm and decreased the level in the nucleus, which was reversed by the treatment of 2-D08. Conversely, UBE2I knockdown and N106 treatment had the opposite effect.
CONCLUSIONS: UBE2I modulated the nuclear translocation of hnRNPA2B1 by promoting SUMOylation in OA.

Ankle osteoarthritis is a relatively understudied condition and the molecular mechanisms involved in its development are not well understood. This investigation aimed to explore the role and underlying molecular mechanisms of Yes-associated protein (YAP) in rat ankle osteoarthritis. The results demonstrated that YAP expression levels were abnormally increased in the ankle osteoarthritis cartilage model. In addition, knockdown of YAP expression was shown to hinder the imbalance in ECM metabolism induced by IL-1β in chondrocytes, as demonstrated by the regulation of matrix metalloproteinase (MMP)-3, MMP-9, and MMP-13, a disintegrin, metalloprotease with thrombospondin motifs, aggrecan, and collagen II expression. Additional studies revealed that downregulation of YAP expression markedly inhibited the overexpression of β-catenin stimulated by IL-1β. Furthermore, inhibition of the Wnt/β-catenin signaling pathway reversed the ECM metabolism imbalance caused by YAP overexpression in chondrocytes. It is important to note that the YAP-specific inhibitor verteporfin (VP) significantly delayed the progression of ankle osteoarthritis. In conclusion, the findings highlighted the crucial role of YAP as a regulator in modulating the progression of ankle osteoarthritis via the Wnt/β-catenin signaling pathway. These findings suggest that pharmacological inhibition of YAP can be an effective and critical therapeutic target for alleviating ankle osteoarthritis.