Gαs regulates Wnt/β-catenin and Hh signaling in mesenchymal stem cell fate choices under homeostasis and disease

Friday, November 08, 2013 — Poster Session III
10:00 a.m. – 12:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NHGRI	STEMCELL-9

Authors

D. Malhotra
J.B. Regard
J. Gvozdenovic-Jeremic
M. Josey
M. Chen
L.S. Weinstein
J. Lu
E.M. Shore
F.S. Kaplan
Y. Yang

Abstract

Bone formation is exquisitely controlled in space. Heterotopic ossification (HO), the pathologic formation of extra-skeletal bone after trauma or in rare genetic disorders is disabling and lethal; however, the molecular mechanisms that spatially restrict bone formation are unknown. In the bone deformation disorder fibrous dysplasia (FD), we showed that gain of function mutations of GNAS that encodes Gαs upregulated Wnt/β-catenin signaling, accompanied by a decline in osteogenic differentiation from defective skeletal progenitors. Here, we identify ectopic Hedgehog (Hh) signaling as a seminal cause of HO in mouse models of progressive osseous heteroplasia (POH) that results from null mutations of Gαs. Inactivation of Gαs decreased cAMP-driven PKA activity, and stimulated Hh targets by activating Gli2 and inhibiting Gli3 repressor formation. Additionally, we observed a decline in Wnt/β-catenin targets that accompanied an accelerated osteogenic differentiation from spatially inappropriate mesenchymal progenitors. Moreover, in POH patient samples, Hh signaling was upregulated in ectopic osteoblasts; and in animal models, ectopic activation of Hh signaling was sufficient to induce HO, while genetic inhibition of Hh signaling blocked HO. Our findings identify Gαs as a necessary and sufficient regulator of osteoblast differentiation from mesenchymal progenitors by maintaining a balance between two key signaling pathways: Wnt/β-catenin and Hh.