Matrix gla protein (MGP), a potent inhibitor of extracellular matrix (ECM) mineralization, is primarily produced by vascular smooth muscle cells (VSMCs) and chondrocytes. Consistent with its expression profile, MGP deficiency in mice (Mgp-/- mice) results in extensive mineralization of all arteries and cartilaginous ECMs. Interestingly, we observed a progressive loss of body weight in Mgp-/- mice, which becomes apparent by the third week of age. Taking into account the new paradigm linking the metabolic regulators of energy metabolism and body mass to that of bone remodeling, we compared the bone volume in Mgp-/- mice to that of their wild type littermates by micro-CT and bone histomorphometry. We found a decrease of bone volume over tissue volume in Mgp-/- mice caused by an impaired osteoblast function. In culture, early differentiation of Mgp-/- primary osteoblasts was not affected; however there was a significant upregulation of the late osteogenic marker Bglap (osteocalcin). We examined whether the prevention of arterial calcification in Mgp-/- mice could correct the low bone mass phenotype. The bones of two different genetic models: Mgp-/-;SM22-Mgp and Mgp-/-;Eln+/- mice were analyzed. In the former strain, vascular calcification was fully rescued by transgenic overexpression of Mgp in the VSMCs, while in the latter, elastin haploinsufficiency significantly impeded the deposition of minerals in the arterial walls. In both models, the low mass phenotype seen in Mgp-/- mice was rescued. Our data support the hypothesis that the arterial calcification, not MGP deficiency itself, causes the low bone mass phenotype in Mgp-/- mice. Taken together, we provide evidence that arterial calcification affects bone remodeling and pave the way for further mechanistic studies to identify the pathway(s) regulating this process.
Keywords: BFR/BS; BMD; BV/TV; Bone remodeling; ECM; ESRD; Eln; MAR; MGP; Matrix gla protein (MGP); Ob/B.Pm; Ob/T.Ar; Oc/B.Pm; TB; TRAP; Toluidine blue; VKVG; VSMCs; Vascular calcification; bone formation rate over bone surface; bone mineral density; bone volume over tissue volume; elastin; end-stage renal disease; extracellular matrix; matrix gla protein; mineral apposition rate; osteoblasts per bone perimeter; osteoblasts per tissue area; osteoclasts per bone perimeter; osteoclasts per tissue area; tartrate resistant acid phosphatase; vascular smooth muscle cells; von Kossa and van Gieson.
© 2013.