YAP and TAZ Promote Periosteal Osteoblast Precursor Expansion and Differentiation for Fracture Repair

Abstract

In response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development. However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing in mice. Constitutive YAP and/or TAZ deletion from Osterix‐expressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture or by developmental deficiencies in the progenitor cell pool before fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset‐inducible knockout mice (using Osx‐CretetOff) in which YAP and TAZ were deleted before fracture but after normal development. Adult onset‐induced YAP/TAZ deletion had no effect on cartilaginous callus formation but impaired bone formation at 14 days post‐fracture (dpf). Earlier, at 4 dpf, adult onset‐induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset‐induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf before the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. © 2020 American Society for Bone and Mineral Research (ASBMR).

Wnt1 Boosts Fracture Healing by Enhancing Bone Formation in the Fracture Callus

“…Both signaling pathways are known for their strong osteoanabolic effects during bone regeneration. (7,(36)(37)(38)(39) On the other hand, known inhibitors of canonical Wnt signaling (eg, Dkk1, Dkk3, Sclerostin) were also significantly enriched in the fracture callus, although these molecules were shown to have a negative effect on fracture healing. (10,14,40,41) This might be due to a negative feedback loop for self-regulation of the pathway.…”

Drug repositioning of polaprezinc for bone fracture healing

“…They showed that YAP and TAZ coordinately enhanced osteoblast activity and osteoclast-mediated bone remodeling to promote bone development 48 . In addition, YAP appears to be involved in the expansion and differentiation of periosteal osteoblastic precursor cells in order to promote bone fracture healing 49 . Interestingly, YAP has been shown to be associated with the osteocyte-mediated bone remodeling processes by regulating the mechanical properties of bone matrix organization 50 .…”

YAP/TAZ in Bone and Cartilage Biology

“…Finally, YAP/TAZ could contribute to bone fracture healing because YAP/TAZ deletion in adult mice impaired bone formation in the callus ( Kegelman et al, 2021 ). Thus, YAP/TAZ accelerated bone fracture healing via the expansion and differentiation of periosteal osteoblast precursors.…”