C-Type natriuretic peptide overexpression protects mice against post-ovariectomy osteoporosis.

C-type natriuretic peptide (CNP) signaling pathway has been shown to regulate endochondral bone growth and has been proposed to promote bone formation through regulation of osteoblast function. A transgenic mouse (CNPcol2a1TG) that over-expresses CNP by a Col2a1 promoter and enhancer was generated resulting in increased trabeculation in the subchondral bone. We hypothesized that CNPcol2a1TG female mice might resist to bone loss due to estrogen deficiency post-ovariectomy (OVX) and rescue post menopausal osteoporosis. CNPcol2a1TG female and wild type were ovariectomized and sham operated at 1.5 month of age to induce post menopausal osteoporosis. CNPcol2a1TG and wild type littermate mice were analysed in vivo and in vitro using methods of skeletal staining, x-rays, micro-CT and using serologic measures of bone remodeling. Primary chondrocyte and osteoblast cultures isolated from rib cartilage and calvarium of newborn CNPcol2a1TG and wild type littermates were analysed for mRNA and protein expressions of molecules that play roles in bone remodeling. The serum osteocalcin levels of CNPcol2a1TG mice both OVX and sham operated were significantly high as compared to wild-type OVX and sham operated littermates. Micro-CT analysis of the thoracic spine (6-7) of overictomized mice showed increased cortical and trabecular bone mineral content, in CNPcol2a1TG which remained higher even after OVX as compared to wild type sham and ovx littermates. Average trabecular thickness and connectivity in CNPcol2a1TG mice was highest compared to OVX CNPcol2a1TG, wild type sham, ovx. Quantitative RT-PCR suggested a possible regulatory effect of CNP in bone remodelling. Furthermore, ratio of OPG and RANKL was higher in the transgenic mice suggesting suppression of osteoclastogenesis in the transgenic mice compared to wild type. In conclusion, these results suggest that CNP might have a therapeutic role in post menopausal osteoporosis by affecting the bone mineralization and trabeculation