Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Joel D. Boerckel

Abstract

During bone growth, remodeling, and fracture repair, skeletal lineage cell responses require the coordinated activation of multiple transcriptional programs. As defective genetic regulation of bone formation leads to both developmental and metabolic skeletal diseases, identifying and characterizing novel transcriptional regulators of skeletal growth, remodeling and repair is important to the future development of targeted therapeutics. The functions of the paralogous transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in bone are controversial, with evidence for each either promoting or inhibiting osteogenesis in vitro. Here, we used in vivo mouse models of combinatorial YAP/TAZ deletion from skeletal lineage cells to investigate their physiologic roles in bone growth, remodeling, and fracture repair. First, YAP and TAZ in Osterix-expressing cells combinatorially promoted bone development and growth by regulating osteoblast function, paracrine regulation of osteoclastic remodeling, and bone matrix quality. Furthermore, combinatorial YAP and/or TAZ deletion from Osterix-expressing cells mimicked the clinical skeletal fragility disease, osteogenesis imperfecta, with spontaneous fractures and dysregulated collagen composition leading to reduced bone mechanical properties. Second, YAP and TAZ deletion later in the skeletal lineage, from DMP1-expressing cells, promoted bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated coordination of osteoblast/osteoclast activity and osteocytic perilacunar/canalicular remodeling. Finally, YAP and TAZ in Osterix-expressing cells combinatorially promoted the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. Taken together, these data establish the paralogous transcriptional co-activators, YAP and TAZ, as important regulators of bone formation and function during skeletal growth, remodeling, and fracture repair. Further elucidation of the signaling pathways that control YAP/TAZ-dependent transcriptional regulation during bone function could enable future therapies to reverse skeletal fragility and enhance bone healing.

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