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

Abstract

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⌬) develop lesions that are the consequence of spontaneous bone fracture. We now present a more defined bone phenotype found in MAGP1⌬mice. A longitudinal DEXA study demonstrated age-associated osteopenia in MAGP1⌬ animals and CT confirmed reduced bone mineral density in the trabecular and cortical bone. Further, MAGP1⌬ mice have significantly less trabecular bone, the trabecular microarchitecture is more fragmented, and the diaphyseal cross-sectional area is significantly reduced. The remodeling defect seen in MAGP1⌬ mice is likely not due to an osteoblast defect, because MAGP1⌬ bone marrow stromal cells undergo osteoblastogenesis and form mineralized nodules. In vivo, MAGP1⌬ 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⌬ bone marrow macrophage cells is increased relative to the wild type, and osteoclast differentiation markers are expressed at earlier time points in MAGP1⌬ cells. In vivo, MAGP1⌬ mice have more osteoclasts lining the bone surface.RANKL(receptoractivatorofNF-Bligand)expressionissignificantly higher in MAGP1⌬ bone, and likely contributes to enhanced osteoclastogenesis. However, bone marrow macrophage cells from MAGP1⌬ 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.Originally thought to serve a purely structural role, the extracellular matrix (ECM) 2 is now known to be an important regulator of tissue development and homeostasis. Microfibrils are an abundant component of the ECM and can be found alone as microfibril bundles or associated with elastin in elastic fibers. Three fibrillins (FBN1, -2, and -3) provide the major structural components of these 10 nm diameter fibrils (1-3), although numerous microfibril-associated proteins interact with fibrillin and contribute to microfibril function. Fibrillin expression is widespread throughout development and is a product of most mesenchymal/interstitial cells (4). In the developing skeletal system, fibrillin expression has been documented in limb bud development, as well as in the adult bone (1, 5). Within the bone, fibrillin microfibrils can be found in the periosteal matrix, surrounding osteocytes, chondrocytes, and osteons, on the endochondral surface, and within the trabecular matrix (7). Microfibrils have clinical significance as mutations in the fibrillin genes give rise to a number of heritable connective tissue disorders. Mutations in the gene for fibrillin-1, for example, are linked to M...

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

“…Loss of MAGP2 Alone Does Not Significantly Alter Bone Mass or Architecture-Mice lacking MAGP1 are osteopenic by 6 months of age, with a high incidence of spontaneous fractures (13,20). Spontaneous fractures are not observed in 2KO or DKO mice, and the skeleton appears grossly normal.…”

“…This contrasts with 1KO mice, which have complex phenotypes, including hematopoietic defects, obesity, and abnormal bone homeostasis (13,19,20). To investigate whether 2KO mice have defects in hematopoiesis, antibody labeling and flow cytometry were used to assess the complement of hematopoietic cells in the peripheral blood circulation or in spleen tissue.…”

“…MAGP1 binds TGF␤s, BMPs, and Notch receptors and ligands (13,33). Much like the classical fibrillinopathies, MAGP1 loss of function leads to increased TGF␤ signaling and subsequent disease in some tissues (4,13,19,20). Like MAGP1, MAGP2 also binds TGF␤ superfamily members as well as Notch receptors and ligands.…”

“…Genetic deletion of extracellular MAGP1 in mice results in an array of phenotypes, including a bleeding diathesis, obesity, and osteopenia (13,19,20). MAGP1-deficient animals also have a pronounced deficiency in circulating and tissue monocytes.…”

Extracellular Microfibrils Control Osteoblast-supported Osteoclastogenesis by Restricting TGFβ Stimulation of RANKL Production

“…Relevant to the last group of extrinsic factors, gene function studies in mice have shown that collagen I fibrillogenesis is a critical contributor to bone mass and strength (21)(22)(23)(24)(25)(26); that osteonectin supports osteoblast formation, maturation, and survival (27); that biglycan is involved in preosteoblast differentiation and osteoblast-supported osteoclastogenesis (28,29); that osteopontin participates in stimulating osteoclast motility and bone resorption (30); and that MAGP1 restricts osteoclast differentiation and activity (31). Our own genetic studies have recently demonstrated that fibrillin-1 and fibrillin-2 support osteoblast maturation and bone formation by controlling local TGF␤ and BMP bioavailability (32).…”