Modulating mechanobiology as a therapeutic target for synovial fibrosis to restore joint lubrication

Bonnevie, Edward D.; Scanzello, Carla R.; Mauck, Robert L.

doi:10.1016/j.joca.2023.09.012

Cited by 3 publications

(2 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study proposes a potential therapeutic avenue for managing osteoarthritic pain by targeting the CD39+CD55− cell population. This suggestion aligns with recent studies that have explored a small-molecule inhibitor targeting ROCK to mitigate the transition from fibroblasts to myofibroblasts in diseased synovial tissue [39]. Decreasing the CD39+CD55− cell population may indeed hold promise, but further research is necessary to validate this approach.…”

Section: Discussionsupporting

confidence: 79%

“…Synovial fibrosis factor is responsible for causing joint pain and stiffness in arthritis [38]. A prior study proposed that when synovial fibroblasts are exposed to stiffer environments due to fibrosis, their characteristics deviate from their essential role in producing lubricating substances [39]. It is well established that lubricin, encoded by the PRG4 gene, plays a crucial role in regulating cartilage health [40,41].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

Tsuchiya,

Ohashi,

Kodera

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Recent studies utilizing single-cell analysis have unveiled the presence of various fibroblast (Fb) subsets within the synovium under inflammatory conditions in osteoarthritis (OA), distinguishing them from those in rheumatoid arthritis (RA). Moreover, it has been reported that pain in knee OA patients is linked to specific fibroblast subsets. Single-cell expression profiling methods offer an incredibly detailed view of the molecular states of individual cells. However, one limitation of these methods is that they require the destruction of cells during the analysis process, rendering it impossible to directly assess cell function. In our study, we employ flow cytometric analysis, utilizing cell surface markers CD39 and CD55, in an attempt to isolate fibroblast subsets and investigate their relationship with OA pathology. Synovial tissues were obtained from 25 knee OA (KOA) patients. Of these, six samples were analyzed by RNA-seq (n = 3) and LC/MS analysis (n = 3). All 25 samples were analyzed to estimate the proportion of Fb (CD45−CD31−CD90+) subset by flow cytometry. The proportion of Fb subsets (CD39+CD55− and CD39−CD55+) and their association with osteoarthritis pathology were evaluated. CD39+CD55− Fb highly expressed myogenic markers such as CNN1, IGFBP7, MYH11, and TPM1 compared to CD39−CD55+ Fb. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of upregulated differentially expressed genes (DEGs) in CD39+CD55− Fb identified the Apelin pathway and cGMP-PKC-signaling pathway as possibly contributing to pain. LC/MS analysis indicated that proteins encoded by myogenic marker genes, including CNN1, IGFBP7, and MYH11, were also significantly higher than in CD39−CD55+ Fb. CD39−CD55+ Fb highly expressed PRG4 genes and proteins. Upregulated DEGs were enriched for pathways associated with proinflammatory states (‘RA’, ‘TNF signaling pathway’, ‘IL-17 signaling pathway’). The proportion of CD39+CD55− Fb in synovium significantly correlated with both resting and active pain levels in knee OA (KOA) patients (resting pain, ρ = 0.513, p = 0.009; active pain, ρ = 0.483, p = 0.015). There was no correlation between joint space width (JSW) and the proportion of CD39+CD55− Fb. In contrast, there was no correlation between the proportion of CD39−CD55+ Fb and resting pain, active pain, or JSW. In conclusion, CD39+CD55− cells exhibit a myofibroblast phenotype, and its proportion is associated with KOA pain. Our study sheds light on the potential significance of CD39+CD55− synovial fibroblasts in osteoarthritis, their myofibroblast-like phenotype, and their association with joint pain. These findings provide a foundation for further research into the mechanisms underlying fibrosis, the impact of altered gene expression on osteoarthritic joints, and potential therapeutic strategies.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

Tsuchiya,

Ohashi,

Kodera

et al. 2023

Biomedicines

View full text Add to dashboard Cite

show abstract

Gentiopicroside Ameliorates Synovial Inflammation and Fibrosis in Koa Rats by Modulating the Hmgb1-Mediated Pi3k/Akt Signaling Axis

Wei,

Ma,

Kang

et al. 2024

Preprint

View full text Add to dashboard Cite

IL24 Expression in Synovial Myofibroblasts: Implications for Female Osteoarthritis Pain through Propensity Score Matching Analysis

Shibata,

Ohashi,

Tsukada

et al. 2024

Medicina

View full text Add to dashboard Cite

(1) Introduction: Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) Methods: To assess gender-specific variations, we analyzed myofibroblast marker expression and IL24 levels in synovial tissue samples from propensity-matched male and female OA patients (each n = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between IL24 expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between IL24 and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients (n = 5), and IL24 expression was compared between these subsets. (3) Results: Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and IL24 compared to males. IL24 expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed IL24 compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) Conclusions: Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA’s multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.

show abstract

Modulating mechanobiology as a therapeutic target for synovial fibrosis to restore joint lubrication

Cited by 3 publications

References 45 publications

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

Gentiopicroside Ameliorates Synovial Inflammation and Fibrosis in Koa Rats by Modulating the Hmgb1-Mediated Pi3k/Akt Signaling Axis

IL24 Expression in Synovial Myofibroblasts: Implications for Female Osteoarthritis Pain through Propensity Score Matching Analysis

Contact Info

Product

Resources

About