Bone Abstracts

GNAS-Gsalpha based disorders lead to heterogeneous diseases associated with abnormal bone development via two distinct mechanisms. At the level of the growth plate in bones, the PTHrP/PTH1R/Gsalpha/cAMP/PKA/PDE signalling pathway regulates endochondral ossification. PTHrP binds to the PTH receptor (PTH1R) which then couples with the stimulatory G protein (Gsalpha) leading to cAMP formation. cAMP binds to the regulatory 1A subunits (R1A) of the PKA. Upon binding the catalytic subunits dissociate from the R1A and phosphorylate numerous target proteins including CREB, which activates transcription of cAMP responsive genes. Phosphodiesterases (PDE’s) regulate intracellular cAMP levels. Down-regulation of this signalling pathway due to mutations or methylation changes in genes coding for proteins spanning throughout the pathway from PTH1R (Blomstrand dysplasia) to PDE’s (acrodysostosis) lead to end-organ resistance to the action of PTHrP, abnormal endochondral ossification thus resulting in various degrees of chondrodysplasia. Other then chondrodysplasia, another hallmark of GNAS based disorders are de novo formations of extra skeletal qualitatively normal bone in skin and subcutaneous fat due to abnormal differentiation of mesenchymal stem cells (MSC’s). Based on studies from transgenic mice, Gsalpha seems to be a key regulator of osteoblast differentiation by maintaining the balance between two key signalling pathways: Wnt-beta catenin and Hedgehog. Gsalpha’s role may be to prevent bone formation in tissues where bone should not form. Historically most GNAS based diseases were classified under the term pseudohypoparathyroidism (PHP). Recently, a novel classification including a larger span of diseases, based on their common mechanism, was proposed using the term inactivating PTH/PTHrP signalling disorders (iPPSD).

Disclosure: I have received honoraria and travel grant from Kyowa Kirin and Ultragenyx.