Platelet-derived growth factor receptors (PDGFRs) play essential roles in embryogenesis, regulating the proliferation, migration, survival and differentiation of many cell types. Not surprisingly, humans with gain-of-function mutations in PDGFRB exhibit a spectrum of phenotypes, many of which affect the skeleton and other connective tissues. Now, Hae Ryong Kwon and co-workers report that, in mice, a D849V gain-of-function mutation in Pdgfrb causes skeletal phenotypes associated with intrinsic changes in skeletal stem cells (SSCs). They first reveal that PDGFRβD849V mice show perturbed skeletal growth, exhibiting wasting and overgrowth phenotypes. They further show that SSCs isolated from PDGFRβD849V mice exhibit colony formation defects that parallel these phenotypes, suggesting that SSC-intrinsic defects mediate the skeletal phenotypes. Using scRNA-seq, the researchers also report that, whereas wild-type SCCs exhibit multilineage potential, mutant SSCs show altered osteogenic potential, with osteogenesis-related genes being downregulated in these cells. Moreover, mutant cells undergo poor osteogenesis in vitro and instead show increased expression of chondrogenic markers and enhanced osteoclastogenesis. Finally, the authors show that the PdgfrbD849V mutation causes increased STAT5 phosphorylation and overexpression of Igf1, suggesting that the STAT5-IGF1 axis is implicated in PDGFRβ-mediated overgrowth. Together, these findings highlight that elevated PDGFR signalling in SSCs can alter stem cell functions to give rise to skeletal disorders.
