The Skeletal Stem Cell Basis for Skeletal Fragility
Abstract
This project will address Musculoskeletal Disorders, which is a Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area. Here, we will conduct a mechanistic study elucidating the cellular basis of bone to fat tissue remodeling observed in skeletal fragility disorders of low bone mass such as osteoporosis. This study is in alignment with FY22 PRMRP Strategic Goals under Foundational Studies, which focuses on understanding mechanisms underlying the pathobiology of associated musculoskeletal disorders. Critical Problem: Osteoporosis is a skeletal disorder resulting in bone fragility and increased fracture risk. A signature feature of osteoporosis and many other skeletal disorders (such as aging-associated bone loss, glucocorticoid-induced bone loss, irradiation, and anorexia nervosa) is bone loss with a gain in marrow fat content. The collective impact of these disorders is tremendous. Although osteoporosis is more prevalent in women (8 million, 1 in 5 U.S. women), it also affects over 2 million American men. Among these patients, half of all women and a quarter of men aged 50 years or more, will encounter lifetime fracture. These fractures cause deadly complications such as pneumonia, blood clots, and postoperative complications that ultimately lead to death. In the United States, Veterans are at a higher risk of developing osteoporosis compared to civilian populations due to their lifestyle and health issues related to military service, such as excessive alcohol use, spinal cord injury, lack of weight-bearing exercise, obesity, and prolonged corticosteroid use. Current treatment options for osteoporosis and other disorders of low bone mass have strong limitations due in part to both the few anabolic agents available and the restrictions on the use of these agents, necessitating new approaches to understand the pathogenesis of and therapeutic targets for these disorders. New insights into basic bone biology for osteoporosis will lead to therapeutic advances for this disorder. Innovation: In this project, we will scientifically perform mechanistic studies to understand the pathobiology of bone to fat tissue remodeling occurring in osteoporosis or other disorders of low bone mass. Here, we will provide first direct determination of the cellular basis for the decrease in the bone-forming cells, osteoblasts, and the increase in fat containing cells in the marrow, adipocytes, that lies in the heart of various disorders of low bone mass. A core innovation underlying this project is providing a key insight into the identity of a candidate adipocyte/osteoblast bipotent cell by combining all the markers that define current skeletal stem cells (SSCs) and adipocyte progenitors. Our work provides key evidence that heterogeneity exists within the current SSC definition and will further divide it into true stem and non-stem fractions. This work will also harness technical innovations to accomplish project goals, including utilization of 18+ color FACS (Fluorescence Assorted Cell Sorting) for deep phenotypic segregation of SSCs and a combination of novel in vivo transplantation used together with high-resolution 3D tissue imaging to allow for unambiguous resolution of the in vivo adipogenic capacity of specific cell populations. Impact: In summary, this project will provide the first identification of this key cell where the decision to form bone-forming osteoblasts versus fat-forming adipocytes occurs, and the first resolution of the cellular pathogenesis of osteoporosis and related disorders down to key specific cellular populations. This study will be a paradigm-establishing discovery, as it will enable the first direct determination of the cellular basis for the decrease in bone-forming osteoblasts and increase in fat-forming adipocytes that lies at the heart of osteoporosis and other related disorders of low bone mass. This mechanistic insight into the cellular basis of skeletal tissue remodeli
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310002
Entities
People
- Shawon Debnath
Organizations
- United States Army
- Weill Cornell Medicine