Targeting YAP-Hhip-mediated osteogenesis in Gli1+ osteogenic progenitors suppresses aberrant subchondral bone remodeling in osteoarthritis.

OBJECTIVE

The role of Yes-associated protein (YAP) in osteoblasts during subchondral bone remodeling in aberrant mechanical loading-induced osteoarthritis (OA) was investigated.

METHODS

We generated Gli1-CreERT2;YAPfl/fl mice, in which deletion of Yap blocked the YAP signaling in the Gli1+ cell lineage. A mouse model with osteoarthritis (OA)-like changes in the temporomandibular joint (TMJ) was induced by partial discectomy (PD). Smoothened agonist administration was also used intraperitoneally after PD. Micro-computed tomography, histological analysis, immunofluorescence staining, and RNA-seq were conducted for analyses.

RESULTS

Our study found that YAP, co-expressed with Gli1+ osteogenic progenitors, was important for maintaining condylar bone microstructure during bone homeostasis. Furthermore, in a TMJOA mouse model, an early and substantial increase in YAP activity (0.6443 [95% confidence interval (CI): 0.5673 to 0.7212]), followed by a reduction in Hhip expression (-0.04583 [95%CI: -0.06482 to -0.02683]) and subsequent increase in osteogenesis (0.05554 [95%CI: 0.04231 to 0.06877]), was consistently alongside abnormal subchondral bone remodeling. Critically, specific inhibition of YAP activity in Gli1+ osteogenic progenitors could maintain the expression of Hhip (0.004732 [95%CI: -0.02302 to 0.03249]), inhibit the excessive osteogenesis (0.06062 [95%CI: 0.02971 to 0.09153]), and eventually mitigate the abnormal subchondral bone changes and cartilage degradation. Furthermore, additional activation of Hh-Gli1 signaling could further aggravate the rescued OA phenotype in subchondral bone.

CONCLUSIONS

Our findings demonstrated that YAP plays a critical role in subchondral bone remodeling in mice. Furthermore, targeting the YAP-Hhip axis through regulation of Hh-Gli1 signaling in Gli1+ osteogenic progenitors could inhibit OA progression. This may offer new therapeutic insights for treating OA in mice.