title: 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 (MAGP1Delta) develop lesions that are the consequence of spontaneous bone fracture. We now present a more defined bone phenotype found in MAGP1Delta mice. A longitudinal DEXA study demonstrated age-associated osteopenia in MAGP1Delta animals and muCT confirmed reduced bone mineral density in the trabecular and cortical bone. Further, MAGP1Delta 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 MAGP1Delta mice is likely not due to an osteoblast defect, because MAGP1Delta bone marrow stromal cells undergo osteoblastogenesis and form mineralized nodules. In vivo, MAGP1Delta 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 MAGP1Delta bone marrow macrophage cells is increased relative to the wild type, and osteoclast differentiation markers are expressed at earlier time points in MAGP1Delta cells. In vivo, MAGP1Delta mice have more osteoclasts lining the bone surface. RANKL (receptor activator of NF-kappaB ligand) expression is significantly higher in MAGP1Delta bone, and likely contributes to enhanced osteoclastogenesis. However, bone marrow macrophage cells from MAGP1Delta mice show a higher propensity than do wild-type 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Clarissa S
authors.initials: CS
authors.lastname: Craft
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Marcus
authors.initials: M
authors.lastname: Watkins
authors.forename: Susan
authors.initials: S
authors.lastname: Grimston
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brodt
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Broekelmann
authors.forename: Justin S
authors.initials: JS
authors.lastname: Weinbaum
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pierce
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016723:Bone Remodeling; D003285:Contractile Proteins / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D000071837:Fibrillins; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D025941:Protein Interaction Mapping; D053245:RANK Ligand / Q000378:metabolism; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000071837:Fibrillins; D008840:Microfilament Proteins; D016328:NF-kappa B; D053245:RANK Ligand; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta; C016598:microfibrillar protein