Abstract

GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsa) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsa, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsa activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsa mutant (Gsa-R201H) conditionally upon Cre recombinase (cGsaR201Hmice). Gsa-R201H was expressed in cultured bone marrow stromal cells from cGsaR201Hmice upon adenoviral-Cre transduction. When crossed with mice in which Cre is expressed in a tamoxifen-regulatable fashion (CAGGCre-ER™), tamoxifen injection resulted in mosaic expression of the transgene in double mutant offspring. We then crossed the cGsaR201Hmice with Prx1-Cre mice, in which Cre is expressed in early limb-bud mesenchyme. The double mutant offspring displayed short limbs at birth, with narrow hypertrophic chondrocyte zones in growth plates and delayed formation of secondary ossification center. Consistent with enhanced Gsa signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsa activity during limb development disrupts endochondral ossification and bone growth. Given that Gsa haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsa activity is essential for normal growth plate physiology.

View details for PubMedID 29471062