Osteocytes serve as the primary mechanosensors in bone, coordinating bone formation and resorption in response to mechanical demands; however, this coordination is lost in metabolic bone diseases such as osteoporosis, leading to reduced bone mass and increased fracture risk. Most current clinical treatments target inhibition of bone resorption, but osteoporosis is characterized by defects in multicellular coordination, orchestrated by the mechanotransductive osteocytes. The long-term objective of this project is to understand the mechanisms by which osteocytes transduce mechanical signals to regulate skeletal homeostasis, which may lead to therapies that can restore the balance in osteoporotic bone. Recent studies by the PI demonstrate that the mechanosensitive transcription factors Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) have mutually compensatory roles in skeletal development, but their roles late in the skeletal cell sequence, in the osteocyte, have not been studied. We hypothesize that osteocyte YAP and TAZ are critical for bone adaptation to mechanical loading and that drugs that inhibit YAP/TAZ activity for cancer treatment may affect bone health. This hypothesis will be tested in two specific aims:
Aim 1 will determine the roles of osteocyte YAP and TAZ in bone adaptation to mechanical loads. These studies will employ the mouse tibial loading model in which dynamic application of mechanical forces induces both cortical and trabecular bone adaptation. By conditional ablation of YAP, TAZ and candidate co-effectors from osteocytes, these studies will reveal, for the first time, the roles of these proteins in osteocyte function. Using a combination of biomechanical, genetic, and molecular biology approaches, we will identify the molecular effectors of YAP/TAZ-mediated mechanotransduction in osteocytes in vivo.
Aim 2 will determine whether pharmacological YAP/TAZ inhibition impairs bone adaptation. Pharmaceutical targeting of YAP/TAZ activation shows promise as an anti-cancer therapy; however, cancer treatment-induced osteoporosis is a common side effect of anti-cancer therapies, and may be induced by drugs that inhibit YAP/TAZ activation. Therefore, understanding the influence of these drugs on bone homeostasis and remodeling will be essential for assessing drug safety and efficacy. Together, these studies will establish a novel mechanotransductive signaling pathway in the osteocyte, and will significantly impact our understanding of osteocyte control of bone formation, homeostasis, and mechanical adaptation, with broad implications for metabolic bone disease and anti-cancer therapy.

Public Health Relevance

This project will provide fundamental insights into the mechanisms that underlie osteocyte sensation of mechanical stimuli to direct bone adaptation, and will elucidate the effects of new anti-cancer drugs on bone remodeling and osteoporosis. These studies will have broad implications for osteoporosis and other diseases including cancer treatment-induced bone loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR071559-01A1
Application #
9456011
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Nicks, Kristy
Project Start
2018-05-15
Project End
2020-04-30
Budget Start
2018-05-15
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104