Yap induces osteoblast differentiation by modulating Bmp signalling during zebrafish caudal fin regeneration

Abstract

Osteoblast differentiation is a key process for bone homeostasis and repair. Multiple signalling pathways have been associated with osteoblast differentiation, yet much remains unknown on how this process is regulated in vivo. Previous studies have proposed that the Hippo pathway transcriptional co-activators YAP and TAZ maintain progenitor stemness and inhibit terminal differentiation of osteoblasts, whereas others suggest they potentiate osteoblast differentiation and bone formation. Here, we use zebrafish caudal fin regeneration as a model to clarify how the Hippo pathway regulates de novo bone formation and osteoblast differentiation. We demonstrate that Yap inhibition leads to accumulation of osteoprogenitors and prevents osteoblast differentiation in a cell non-autonomous manner. This effect correlates with a severe impairment of Bmp signalling in osteoblasts, likely by suppressing the expression of the ligand bmp2a in the surrounding mesenchymal cells. Overall, our findings provide a new mechanism of bone formation through the Hippo-Yap pathway, integrating Yap in the signalling cascade that governs osteoprogenitor maintenance and subsequent differentiation during zebrafish caudal fin regeneration.

Role of Hippo-YAP Signaling in Osseointegration by Regulating Osteogenesis, Angiogenesis, and Osteoimmunology

“…Hippo-YAP signaling pathway is also involved in osteoblast differentiation through multiple biological mechanisms. The suppression of YAP may induce lowering ligand bmp2a in MSCs, leading to a severe damage of Bmp signals in osteoblasts nearby, which downregulates osteoblast differentiation through a cell non-autonomous way (Brandão et al, 2019). In a recent vivo study it is demonstrated that suppression of OLFML1, a missense mutant gene in patients with congenital scoliosis, leads to the nuclear translocation of YAP thus promoting expression of target genes and results in an accelerated mineralization process of osteoblasts, suggesting OLFML1 inhibits bone development through a biomechanical mechanism dependent on Hippo-YAP signaling pathway in osteoblasts (Murakami et al, 2018).…”

“…Last but not least, it's worth noticing that Hippo-YAP regulates cellular osteogenic function in not only cell autonomous mode but also non-autonomous mode (Brandão et al, 2019;Wang L. et al, 2020), which further contributes to the complexity of the working manner of Hippo-YAP pathway.…”

Zebrafish: A Suitable Tool for the Study of Cell Signaling in Bone

“…Fin amputation in zebrafish has allowed for in depth examination of the different mechanisms and cellular pathways. The study of Hippo pathway activators YAP and TAZ in fin during osteogenic regeneration demonstrated that YAP induces osteoblast differentiation through the modulation of Bmp signaling [ 41 ].…”

“…However, the different cell signaling effects promoted by Hippo pathway might vary in a context-dependent manner [ 64 ]. In this regard, a zebrafish regeneration model has been used to clarify Hippo pathway’s role in the differentiation and maturation of osteoblast lineage [ 41 ]. The authors, by using the zebrafish caudal fin regeneration model, addressed a new mechanism promoted by Hippo–Yap pathway, suggesting Yap involvement in the signaling cascade regulating osteoprogenitor maintenance and subsequent cell differentiation.…”

“…In particular, they demonstrated that osteoprogenitors rack up, and their differentiation is prevented when Yap is inhibited. On the contrary, Yap expression induces Bmp2a production in mesenchymal cells located in proximal regions, thus enabling BMP signaling activation in adjacent osteoblasts, promoting their maturation [ 41 ].…”