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

Abstract

AbstractAutosomal dominant PDGFRβ 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 PDGFRβ 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 PDGFRβD849V. Mutant SSC colonies undergo poor osteogenesis in vitro and mice with PDGFRβD849V exhibit osteopenia. Increased expression of Sox9 and other chondrogenic markers occurs in SSC colonies from mice with PDGFRβD849V. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFRβD849V SSCs suggests that overgrowth in mice involves PDGFRβD849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFRβD849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.