G_sα is a ubiquitously expressed G protein α‐subunit that couples receptors to adenylyl cyclase. Mice with chondrocyte‐specific ablation of the G_sα gene had severe epiphyseal and growth plate abnormalities and ectopic cartilage formation within the metaphyseal region of the tibia. These results show that G_sα negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH‐rP receptor in growth plate chondrocytes.

Introduction: G_sα is a ubiquitously expressed G protein α‐subunit that mediates signaling through G protein‐coupled receptors to activate the cAMP/protein kinase A signaling pathway. Although studies suggest an important role for G_sα in regulating growth plate development, direct in vivo results examining this role are lacking.

Materials and Methods: The G_sα gene was ablated in murine cartilage by mating mice with loxP sites surrounding the G_sα promoter and first exon with collagen 2a1 promoter‐Cre recombinase transgenic mice. Skeletal tissues were studied by gross and microscopic pathology, and gene expression was determined by in situ hybridization.

Results and Conclusions: Mice with complete chondrocyte‐specific G_sα deficiency (homozygotes) died within minutes after birth and had severe epiphyseal and growth plate defects with shortening of the proliferative zone and accelerated hypertrophic differentiation of growth plate chondrocytes, a phenotype similar to that of PTH/PTH‐related peptide (PTHrP) receptor knockout mice. Indian hedgehog and PTH/PTHrP receptor expression in prehypertrophic chondrocytes was unaffected in mutant mice. PTHrP expression in periarticular cartilage was increased in the mutant mice, probably because of the closer proximity of Ihh‐secreting chondrocytes to the periarticular zone. In addition, these mice developed ectopic cartilage at the anterior side of the metaphyseal region in the tibia. Mice with partial G_sα deficiency (heterozygotes) exhibited no phenotype. These results show that G_sα negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTHrP receptor in epiphyseal and growth plate chondrocytes.