Abstract
The Gs G-protein coupled receptor pathway is a critical regulator of normal bone formation and function. The Gs pathway increases intracellular cAMP levels by ultimately acting on adenylate cyclase. McCune-Albright Syndrome (MAS) and fibrous dysplasia (FD) of the bone are two proto-typical conditions that result from increased cellular Gs signaling activity. Both are caused by somatic activating mutations in the GNAS gene that encodes for the Gsα subunit. FD bone lesions are particularly difficult to treat because of their variability and because of the lack of effective medical therapies. In this review, we briefly discuss the key clinical presentations of FD/MAS. We also review the current status of mouse models that target the Gs GPCR signaling pathway and human cellular models for FD/MAS. These powerful tools and our improving clinical knowledge will allow further elucidation of the roles of GPCR signaling in FD/MS pathogenesis, and facilitate the development of novel therapies for these medically significant conditions.
Highlights
Musculoskeletal disorders such as skeletal dysplasias are a significant health problem affecting both children and adults
G-protein coupled receptors (GPCRs) mediate a wide variety of biological processes and are activated by multiple types of extracellular signals, ranging from photons and ions to small molecules to peptides
GPCRs signal through a select number of canonical pathways [4]: among these, the Gs and Gi pathways increase or decrease intracellular cAMP levels, respectively, by acting on adenylate cyclase, while the Gq pathway increases intracellular calcium by activating phospholipase C
Summary
Musculoskeletal disorders such as skeletal dysplasias are a significant health problem affecting both children and adults. FD/MAS is caused by an acquired somatic mutation in GNAS, the gene that encodes the alpha subunit of the stimulatory G-protein (Gsα), leading to constitutive activation of Gs signaling in affected cells. This mutation occurs post-zygotically, resulting in tissue mosaicism, and is not inherited through the germline. The most common cause is a missense mutation at either position c.602G>A (p.R201H) or c.601C>T (p.R201C) This mutation results in an amino acid substitution in the GTP hydrolase domain of the Gsα protein, inhibiting the intrinsic GTPase activity, and leading to persistently elevated intracellular cAMP levels (Figure 1)
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