The skeleton harbors skeletal stem cells (SSCs) that give rise to all types of cells in the skeletal lineage including chondrocytes, osteoblasts, adipocytes, and bone marrow stromal cells. Understanding the basic biology of SSCs is fundamental for medicine related to bone growth, homeostasis, and regeneration. PDGFRα and PDGFRβ are expressed by SSCs and downstream cell lineages, and loss of PDGF signaling in mice causes defects in skeletal development and fracture repair. More recently, humans with gain-of-function PDGFRβ mutations have been described with a spectrum of skeletal phenotypes ranging from progressive bone loss to skeletal overgrowth. Using conditional knockin mice with a gain-of-function PDGFRβ-D849V mutation, we have shown that Stat1 is a major genetic modifier of skeletal phenotypes. Reducing Stat1 gene dosage in PDGFRβ-D849V mice rescues progressive bone loss and skeletal wasting, and paradoxically results in skeletal overgrowth (He et. al., 2017). SSCs isolated from PDGFRβ-D849V mice exhibit colony formation defects that parallel Stat1-dependent wasting or overgrowth phenotypes in vivo. Using single-cell RNA sequencing on isolated SSCs, we identified local activation of the STAT5-IGF1 axis as a potential mediator of skeletal overgrowth (Kwon et. al., 2021). The growth hormone-STAT5-IGF1-IGF1R signaling circuit is an evolutionarily conserved mediator of somatic growth, metabolism, and tissue repair, which is additionally implicated in aging and cancer. Genetic studies are underway in our lab to elucidate how PDGFR intersects with this circuit.
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