Yap1 Regulates Multiple Steps of Chondrocyte Differentiation during Skeletal Development and Bone Repair

Abstract

Hippo signaling controls organ size and tissue regeneration in many organs, but its roles in chondrocyte differentiation and bone repair remain elusive. Here, we demonstrate that Yap1, an effector of Hippo pathway inhibits skeletal development, postnatal growth, and bone repair. We show that Yap1 regulates chondrocyte differentiation at multiple steps in which it promotes early chondrocyte proliferation but inhibits subsequent chondrocyte maturation both in vitro and in vivo. Mechanistically, we find that Yap1 requires Teads binding for direct regulation of Sox6 expression to promote chondrocyte proliferation. In contrast, Yap1 inhibits chondrocyte maturation by suppression of Col10a1 expression through interaction with Runx2. In addition, Yap1 also governs the initiation of fracture repair by inhibition of cartilaginous callus tissue formation. Taken together, our work provides insights into the mechanism by which Yap1 regulates endochondral ossification, which may help the development of therapeutic treatment for bone regeneration.

Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

“…Previous studies have shown that while early chondrocyte proliferation is promoted, maturation is inhibited 60. This phenomenon is similar to the SMSC-Exos-induced activation of YAP in our study.…”

Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish

“…Because mRNAs were prepared from whole larvae, it is unclear whether this decrease was attributable to that in osteoblasts or chondrocytes. Expression of Col10a1 has been reported to be transcriptionally inhibited by Yap1 (Deng et al, 2016), and our results are consistent with this.…”

“…S7B,D). In addition, we investigated the maturation of osteoblasts and chondrocytes by the expression of col10a1 mRNA, which is known to be inhibited by Yap1 (Deng et al, 2016). There was no significant difference in col10a1 expression between control and ostn ncv105 larvae when examined at 4 dpf by WISH (Fig.…”

Signaling pathways regulating cartilage growth plate formation and activity

“…As a result, YAP1 and TAZ are retained in the cytoplasm and are inactivated [137]. YAP1 serves as a key transcriptional regulator to integrate multiple signaling cascades, including Wnt, TGF-β/BMP, and hedgehog [138]. While a role for TAZ in Runx2-mediated osteogenesis has been well-established, most recently the role of YAP1 in chondrocyte differentiation has also begun to emerge.…”

“…YAP1 can inhibit chondrogenic differentiation through downregulating BMP signaling by suppressing Smads [139]. Furthermore, a most recent mouse genetic study showed that Yap1 promoted chondrocyte proliferation, but inhibited hypertrophy during endochondral ossification and fracture healing [138]. The study shows that Yap1 expression is high in early chondrocyte differentiation and progressively decreases.…”