Title of project

Metabolic regulation of skeletal stem cell function

Abstract

This collaborative project between the laboratory of Ryan Riddle, Ph.D. in the United States and the laboratory of Alexander Rauch, Ph.D. in Denmark seeks to understand how cellular metabolism influences the differentiation of skeletal stem cells. The formation of bone is an energy-intensive process as osteoblasts must synthesize the dense collagen-rich matrix that composes the organic phase of bone and then concentrate the mineral ions that are used to mineralize the tissue. Previous work from the Riddle laboratory documented an essential role for mitochondrial long-chain fatty acid b-oxidation in the formation of bone by mature osteoblasts as mice deficient for an obligate enzyme in b-oxidation specifically in osteoblasts exhibited low bone mass and impaired matrix mineralization. In this proposal, we will examine the necessity of triglyceride synthesis and fatty acid catabolism for the commitment of skeletal stem cells to the osteoblast lineage. Since bone-forming osteoblasts have a relatively short lifespan, the self-renewal and differentiation of skeletal stem cells present in the bone marrow and periosteum to osteoblasts is necessary to keep pace with bone destruction during normal bone remodeling. Understanding the regulators of skeletal stem cell differentiation will facilitate our understanding of age-related bone loss and bone fragility in metabolic diseases. As recent studies and our preliminary data suggest that the formation of a lipid droplet is a key step in the differentiation of stem cells in many tissues, we examine the hypothesis that lipid droplets in skeletal stem cells fuel the early stages of osteoblast differentiation. We leverage the expertise of the Riddle laboratory in the generation of transgenic mouse models to study cellular metabolism and the expertise of the Rauch laboratory in bioinformatic analyses of transcriptional and epigenetic regulation of bone cell differentiation. Our project aligns with the DDEA objectives of using multi-disciplinary, international teams to address complex issues in endocrinology.