| First Author | Karaca A | Year | 2018 |
| Journal | Bone | Volume | 110 |
| Pages | 230-237 | PubMed ID | 29471062 |
| Mgi Jnum | J:262520 | Mgi Id | MGI:6160958 |
| Doi | 10.1016/j.bone.2018.02.016 | Citation | Karaca A, et al. (2018) Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth. Bone 110:230-237 |
| abstractText | GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsalpha) 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 Gsalpha, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsalpha activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsalpha mutant (Gsalpha-R201H) conditionally upon Cre recombinase (cGsalpha(R201H) mice). Gsalpha-R201H was expressed in cultured bone marrow stromal cells from cGsalpha(R201H) mice 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 cGsalpha(R201H) mice 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 Gsalpha signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsalpha activity during limb development disrupts endochondral ossification and bone growth. Given that Gsalpha haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsalpha activity is essential for normal growth plate physiology. |
