Microtubule stabilization targeting regenerative chondrocyte cluster for cartilage regeneration

Abstract

Purpose: Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA). However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown. The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair. Methods and Materials: CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing. The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization. Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration. Results: CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples. Interestingly, the CHs subpopulation namely CHI3L1 + CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process. Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity. Conclusion: These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.

The role of YAP/TAZ on joint and arthritis

“…demonstrated that YAP was up‐regulated in both human OA cartilage and surgery‐induced OA mice cartilage to promote IL‐1β‐induced catabolism, and that the suppression of YAP via YAP siRNA can retard cartilage degradation, decrease chondrocyte apoptosis, and mitigate aberrant subchondral bone formation 152 . This is in agreement with the latest study, which reported that YAP negatively impacts chondrogenesis and chondrocyte regeneration in the OA pathophysiology context, and drug‐induced microtubule stabilization promotes cartilage repair by inhibiting YAP activity in chondrocytes 155 . Similarly, amelioration of OA can be observed when YAP is suppressed by upstream microRNA (miR)‐582‐3p, 153 or inhibitors such as verteporfin 154 .…”

“…152 This is in agreement with the latest study, which reported that YAP negatively impacts chondrogenesis and chondrocyte regeneration in the OA pathophysiology context, and drug-induced microtubule stabilization promotes cartilage repair by inhibiting YAP activity in chondrocytes. 155 Similarly, amelioration of OA can be observed when YAP is suppressed by upstream microRNA (miR)-582-3p, 153 or inhibitors such as verteporfin. 154 Furthermore, elevated YAP1 expression in OA cartilage not only exerts pro-apoptotic and antiproliferative functions, but also inhibits chondrocyte autophagy by interacting with Beclin-1, a crucial regulator T A B L E 3 Effects of TAP/TAZ on the pathogenesis of RA.…”

Advancing skeletal health and disease research with single-cell RNA sequencing

“…Chou et al [ 142 ] found that intact cartilage primarily consists of homeostatic and hypertrophic chondrocyte subpopulation, while damaged cartilage is enriched with prefibrotic- and fibrotic-, regulatory-, reparative- and prehypertrophic-chondrocytes. Subsequently, Wang et al [ 143 ] observed an expansion of CHI3L1 + RegCs in OA, while Li et al [ 144 ] demonstrated the regenerative capacity of CHI3L1 + chondrocytes. Hu et al [ 145 ] uncovered that fibrous cartilage degeneration is primarily induced by fibrocartilage chondrocytes, and ECs were found to predominantly exert immune function in OA.…”