An activating mutation in Pdgfrb causes skeletal stem cell defects with osteopenia andovergrowth in mice

Autosomal dominant PDGFR{beta} gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFR{beta} exhibit SSC colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with the SSC colonies demonstrates alterations in osteoblast and chondrocyte precursors caused by PDGFR{beta}D849V. Mutant SSC colonies undergo poor osteogenesis in vitro and mice with PDGFR{beta}D849V exhibit osteopenia. Increased expression of Sox9 and other chondrogenic markers occurs in SSC colonies from mice with PDGFR{beta}D849V. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFR{beta}D849V SSCs suggests that overgrowth in mice involves PDGFR{beta}D849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFR{beta}D849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.