ESPE Abstracts (2014) 82 WG1.2

The Effect of Stimulatory G Proteins on Differentiation within the Growth Plate

Murat Bastepe

Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA

Endochondral bone formation regulates bone growth both during embryonic development and after birth. Several different autocrine/paracrine or hormonal mechanisms govern the regulation of endochondral bone formation. Among those is the pathway involving stimulatory G protein, which primarily mediates the actions of parathyroid hormone-related peptide (PTHrP) in the growth plate. PTHrP is synthesized in the perichondrial cells and chondrocytes at the end of bones. In the growing bone, chondrocytes proliferate, differentiate, and undergo apoptosis in a coordinated fashion, leading to the formation of bone and its lengthening. PTHrP acts to sustain the proliferative capacity of chondrocytes and inhibit their differentiation through various different mechanisms. The actions of PTHrP are mediated by the G protein coupled PTH/PTHrP receptor. Activation of this receptor causes a GDP–GTP exchange on the alpha-subunit of Gs (Gsα) and, thereby, leads to the dissociation of Gsα from Gβγ subunit. The free, GTP bound Gsα then stimulates the generation of cyclic AMP (cAMP), a ubiquitous second messenger molecule. cAMP molecules bind to the regulatory subunit of protein kinase A (PKA), thus releasing the catalytic subunit. Activated PKA phosphorylates multiple different targets, which collectively mediate the effects of PTHrP in the growth plate. The Gsα-cAMP-PKA signaling pathway is regulated by the activation of cAMP phosphodiesterases, which convert cAMP into AMP. Genetic defects directly affecting the different components of this signaling pathway result in impaired bone growth and are the cause of various skeletal dysplasias in humans, including Blomstrand’s chondro-osteodystrophy, Jansen’s metaphyseal chondrodysplasia, Albright’s hereditary osteodystrophy, acrodysostosis, brachydactyly-mental retardation syndrome, and brachydactyly type E2.

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