Expression of an active Gα_smutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance

Abstract

SignificanceWe generated a novel conditional inducible mouse model of fibrous dysplasia (FD) by expressing mutant GNAS in skeletal stem cells (SSCs) in a temporally controlled and tissue-specific fashion. Typical FD bone lesions developed rapidly in mutant embryos and postnatal mice. GNAS promoted PKA activation and proliferation of SSCs along the osteogenic lineage but impaired their differentiation to mature osteoblasts and triggered increased osteoclastogenesis and bone resorption. FD lesions reverted on cessation of GNAS expression. Thus, GNAS mutation is sufficient and necessary for FD initiation and maintenance. This model provides a valuable opportunity to identify the molecular mechanism underlying FD progression and accelerate the development of more effective treatment options.

RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease

“…(10,16,17) Consequently, inhibition of IL-6 by has been considered as a potential treatment for the disease. (18) Recently, a role for receptor activator of nuclear factor kappa-B ligand (RANKL; a member of the tumour necrosis factor superfamily and a potent stimulator of osteoclastogenesis (19,20) ), in the disease has emerged from studies performed on human skeletal progenitors transduced with G s α R201C , (21) transgenic mice expressing G s α R201C in skeletal cells, (22) and human FD tissue and cells. (23)(24)(25) In addition, serum levels of RANKL have been reported to be increased in mouse models that replicate human FD, (22,26) as well as in FD patients, in which they strongly correlated with the burden of the disease.…”

“…(18) Recently, a role for receptor activator of nuclear factor kappa-B ligand (RANKL; a member of the tumour necrosis factor superfamily and a potent stimulator of osteoclastogenesis (19,20) ), in the disease has emerged from studies performed on human skeletal progenitors transduced with G s α R201C , (21) transgenic mice expressing G s α R201C in skeletal cells, (22) and human FD tissue and cells. (23)(24)(25) In addition, serum levels of RANKL have been reported to be increased in mouse models that replicate human FD, (22,26) as well as in FD patients, in which they strongly correlated with the burden of the disease. (25) Accordingly, a limited number of studies have already tested the effect of the humanized anti-RANKL antibody, denosumab, in FD patients and have reported a positive effect on bone turnover, on the growth rate of lesions, as assessed by CT analysis, and on bone pain.…”

Clinical and translational pharmacological aspects of the management of fibrous dysplasia of bone

“…Fibrous dysplasia/McCune–Albright syndrome (FD/MAS) is a genetic, noninheritable rare bone disease caused by a postzygotic activating mutation of the α subunit of the stimulatory G‐protein (Gsα) . In the skeleton, this results in the overproduction of cAMP in affected cells of the osteogenic lineage, leading to the accelerated production of bone marrow stromal cells (BMSC), while inhibiting the differentiation of these progenitor cells into mature osteoblasts . Despite expressing early osteoblast markers such as alkaline phosphatase (ALP), these immature cells are dysfunctional, leading to the laying down of fibro‐osseous tissue that is under‐mineralized, of poor quality and of disturbed micro‐architecture.…”

“…The unravelling of further aspects of the pathophysiology of FD/MAS has led to exploring potential new pharmacological avenues (Figure ), although the lack of adequate translational tools such as appropriate animal models to test new agents represents the main challenge for the development of novel therapies in the management of FD/MAS .…”

“…A further pathophysiological characteristic of FD lesions is the increased number of osteoclasts present in and around FD lesions, leading to a local increase in bone resorption . The local increase in osteoclastogenesis is believed to be due to the significant up‐regulation of the receptor activator of nuclear factor κ‐B ligand (RANKL) by GNAS ‐mutated osteogenic cells and increased production of interleukin‐6 (IL‐6) by these cells . The observed focal increase in number and clustering of osteoclasts exhibits a tunneling resorption pattern and endosteal fibrosis analogous to changes characteristically observed in hyperparathyroidism .…”