Our lab focuses on identifying new skeletal stem cells and understanding how these stem cells play different protective and pathogenic roles in skeletal diseases.

Approximately half of all women and a fifth of all men will experience a skeletal fracture due to osteoporosis or other diseases causing low bone mass. These fractures kill as many women each year as breast cancer, as fractures often lead to immobility that in turn leads a spiral of progressive deconditioning that can ultimately prove fatal. Improving clinical outcomes in this area will ultimately require finding new therapeutic agents that promote the generation or activity of osteoblasts, the cells that build bone. Ultimately, all bone-forming osteoblasts come from skeletal stem cells, an adult stem cell type that has only recently begun to be studied. A key focus of our work has been the idea that there is not a single skeletal stem cell, but many versions of these cells, each residing in different regions of the skeleton and having distinct contributions to both the normal formation of the skeleton and to the development of skeletal diseases. Our work in this area started with the identification of a new stem cell on the outer surface of bone (Debnath et al., Nature 2018) and is now continuing to identify new stem cells in other regions of the skeleton, including the spine and the skull.

We are also investigating the environmental factors and signals that both support these stem cells and drive their production of bone-forming osteoblasts. In our prior work, we have identified that osteoblasts secrete factors known as SLITs that promote the formation of special blood vessels that in turn tailor the environment in bone to favor new bone formation (Xu et al., Nature Medicine 2018). Accordingly, treatment with SLITs can promote new skeletal blood vessel formation and also reverse bone loss in mouse models of osteoporosis or promote healing in models of fracture repair. In other studies, we have identified a new therapeutic target for the treatment of neurofibromatosis type 1, a disorder whose manifestations include skeletal fragility and impaired fracture healing (Bok et al., Nature Communications 2020). Lastly, we have also identified a new receptor on osteoblasts that regulates responses to a family of proteins, termed the hedgehog family, that provide environmental signals controlling bone formation (Sun et al., Nature Communications 2021). Currently, we are both working to explore how these discoveries may be relevant for the treatment of skeletal disorders and also to identify new therapeutic approaches to increase bone mass and prevent fractures, both in osteoporosis and also in rare genetic diseases of bone.