Musculoskeletal diseases and disorders represent the second leading cause of disability and are a significant clinical burden worldwide. Among these disorders, musculoskeletal injuries can lead to complications in approximately 10% of the cases of bone fractures, and the risk of delayed- or non-union is increased up to 46% when associated with soft tissue and vascular injuries. While muscle is thought to play an important role in bone healing, the mechanisms of action remain poorly understood. There is a large knowledge gap in our understanding of muscle-bone crosstalk in regulating skeletal stem cell function in bone repair.
We aim to elucidate the mechanisms by which muscle injury leads to impaired bone healing in a new muscle-bone injury model in mice that reflects traumatic injury in human. In this model, muscle crush injury severely impacts bone repair by delaying callus formation and stem cell recruitment. We have designed multiple experimental approaches, based on in vitro experiments, state-of-the-art genetic tools for lineage analyses and tissue grafting experiments in order to determine the extent to which traumatic injury in this model affects the coordinated activation and differentiation of skeletal stem cells in bone and adjacent muscle. Through these approaches, we will specifically identify the mechanisms of skeletal stem cell recruitment from muscle and periosteum in the fracture callus (aim 1), characterize the impaired skeletal stem cell activation in muscle and periosteum in the traumatic injury environment (aim 2) and the impact of traumatic injury on cartilage-to-bone transformation during bone regeneration (aim 3). Our work will help determine the causes of non-union associated with polytrauma and may lead to new drug- or cell-based therapies to treat traumatic musculoskeletal injuries and delayed bone healing.

Public Health Relevance

Musculoskeletal diseases and disorders represent the second leading cause of disability worldwide. We aim to elucidate the mechanisms by which muscle injury leads to impaired bone healing in a new muscle-bone injury model in mice that reflects traumatic injury in human. We will determine the extent to which traumatic injury in this model affects the coordinated activation and differentiation of skeletal stem cells in bone and adjacent muscle, and potentially propose new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR072707-02
Application #
9743717
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
2018-07-12
Project End
2023-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Orthopedics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118