Microfibril-associated Glycoprotein-1, an Extracellular Matrix Regulator of Bone Remodeling

MAGP1 is an extracellular matrix protein that, in vertebrates, is a ubiquitous component of fibrillin-rich microfibrils. We previously reported that aged MAGP1-deficient mice (MAGP1 Delta) develop lesions that are the consequence of spontaneous bone fracture. We now present a more defined bone phenotype found in MAGP1 Delta mice. A longitudinal DEXA study demonstrated age-associated osteopenia in MAGP1 Delta animals and mu CT confirmed reduced bone mineral density in the trabecular and cortical bone. Further, MAGP1 Delta mice have significantly less trabecular bone, the trabecular microarchitecture is more fragmented, and the diaphyseal cross-sectional area is significantly reduced. There modeling defect seen in MAGP1 Delta mice is likely not due to an osteoblast defect, because MAGP1 Delta bone marrow stromal cells undergo osteoblastogenesis and form mineralized nodules. In vivo, MAGP1 Delta mice exhibit normal osteoblast number, mineralized bone surface, and bone formation rate. Instead, our findings suggest increased bone resorption is responsible for the osteopenia. The number of osteoclasts derived from MAGP1 Delta bone marrow macrophage cells is increased relative to the wild type, and osteoclast differentiation markers are expressed at earlier time points in MAGP1 Delta cells. In vivo, MAGP1 Delta mice have more osteoclasts lining the bone surface. RANKL(receptor activator of NF-kappa B ligand) expression is significantly higher in MAGP1 Delta bone, and likely contributes to enhanced osteoclastogenesis. However, bone marrow macrophage cells from MAGP1 Delta mice show a higher propensity than do wildtype cells to differentiate to osteoclasts in response to RANKL, suggesting that they are also primed to respond to osteoclast-promoting signals. Together, our findings suggest that MAGP1 is a regulator of bone remodeling, and its absence results in osteopenia associated with an increase in osteoclast number.