Microfibril‐associated glycoprotein‐1 binds multiple active TGF‐beta family members, affecting homeostasis in multiple organ systems

Abstract

Microfibril‐associated glycoprotein‐1 (MAGP‐1) is a small molecular weight extracellular matrix component of the fibrillin‐rich microfibril that forms the scaffold for elastic fibers. Surprisingly, mice null for MAGP‐1 have normal elastic fiber morphology and their elastic tissues function normally. The complex phenotype of mice null for MAGP‐1 includes increased body weight and size due to excess body fat, an altered wound healing response in bone and skin, and a bleeding diathesis. The obesity and bone phenotype is intriguing given the localization of obesity and osteoporosis candidate genes to human chromosome 1, which also houses the MAGP‐1 gene (mfap2). These phenotypic traits are consistent with transforming growth factor‐beta (TGF‐beta) dysregulation, and we have determined that MAGP‐1 binds TGF‐beta and multiple BMPs with high affinity. Further, these traits are opposite to those associated with mutations in MAGP‐1's binding partner fibrillin‐1, and many fibrillin‐1 mutations result in enhanced TGF‐beta signaling. Together, our data implicates MAGP‐1 as an important modulator of microfibril‐mediated growth factor signaling.