Fibrous dysplasia/McCune-Albright syndrome: state-of-the-art advances, pathogenesis, and basic/translational research

Abstract

Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare genetic disease caused by postzygotic activating variants in the GNAS gene, encoding the α subunit of stimulatory G protein (Gα_s). Although multiple organs may be involved, skeletal lesions usually represent the most severe and least treatable expression of the disease, leading to bone deformities, spontaneous fractures, and chronic pain that severely reduce patients' quality of life.The recognition of the causative Gα_s variants and the consequent ligand-independent activation of the adenylyl cyclase/cAMP/PKA pathway has provided a clear molecular explanation to most extra-skeletal pathologies of FD/MAS, leading to the development of effective therapeutic approaches. In contrast, a detailed understanding of the cellular and molecular mechanisms that act downstream of the Gα_s pathway to generate FD bone lesions and clinical expression thereof remain elusive. Multiple key issues remain to be addressed, including some questions that have recently emerged such as the interaction between mutated and non-mutated cells and the role of the latter in the development of the fibrotic tissue.In this review, we provide a summary of the proof-of-concept, preclinical data, and experimental tools that have emerged to date from basic and translational studies on FD and represent the background for future research on the pathogenesis and treatment of this rare disease.

Keywords: Bone remodeling; GNAS; Mouse models; Osteoclastogenesis; Osteogenesis; RANKL; Rare disease; Skeletal stem cell.

Fig. 1

Schematic representation of the α subunit of the stimulatory G protein (Gα_s) pathway at physiological and FD-related pathological conditions. In the basal state, G_s is a heterotrimer composed of GDP-bound Gα_s and a βγ heterodimer. Normally, the G protein is activated upon ligand binding to the G protein coupled receptor (GPCR), which leads to replacement of GDP with GTP and dissociation of GTP-bound Gα_s from Gβ and Gγ. GTP-bound Gα_s activates adenylyl cyclase (AC), leading to intracellular cAMP production. The intrinsic GTPase activity allows the hydrolysis of GTP to GDP and turns off the system. Mutations at R201 and Q227, two residues that are critical for the GTPase activity, lead to constitutive G_s activation by impeding the system to turn-off, leading to excess AC activation and cAMP production even in the absence of ligand binding to GPCR

Fig. 2

Schematic representation of the hypothetical Gα_s-mutated SSC function and differentiation capacity in FD. SSCs are thought to be the source of the osteogenic stroma (FD cells) that accumulate in the bone marrow of FD-affected skeletal segments. Mutated SSCs are able to give rise to osteoblasts but are defective in generating bone marrow adipocytes. The FD cells composing the fibrous tissue may also derive from either differentiated osteoblasts or from the expansion of resident bone marrow fibroblasts (dotted arrows) as result of high bone resorption at bone surfaces

Fig. 3

Histology of FD lesions. (A) Image of a sirius red stained section showing overall morphology of FD lesions with haphazardly distributed bone trabeculae within the fibrotic marrow. (B) High magnification detail of A, showing Sharpey’s fibers (arrows). C, D) Tartrate resistant acid phosphatase (TRAP) staining showing numerous osteoclasts (arrowheads) on the surfaces of and within (i.e. tunneling resorption) bone trabeculae. E, F) TRAP staining showing heterotopic osteoclasts (arrowheads) within the fibrous tissue. ft: fibrous tissue; bt: bone trabecula