Bone morphogenetic protein-1 processes probiglycan

Bone morphogenetic protein-1 (BMP-1) is a metalloprotease that plays import ant roles in regulating the deposition of fibrous extracellular matrix in v ertebrates, including provision of the procollagen C-proteinase activity th at processes the major fibrillar collagens I-III. Biglycan, a small leucine -rich proteoglycan, is a nonfibrillar extracellular matrix component with f unctions that include the positive regulation of bone formation. Biglycan i s synthesized as a precursor with an NH2-terminal propeptide that is cleave d to yield the mature form found in vertebrate tissues. Here, we show that BMP-1 cleaves probiglycan at a single site, removing the propeptide and pro ducing a biglycan molecule with an NH2 terminus identical to that of the ma ture form found in tissues. BMP-1-related proteases mammalian Tolloid and m ammalian Tolloid-like 1 (mTLL-1) are shown to have low but detectable level s of probiglycan-cleaving activity. Comparison shows that wild type mouse e mbryo fibroblasts (MEFs) produce only fully processed biglycan, whereas MEF s derived from embryos homozygous null for the Bmp1 gene, which encodes bot h BMP-1 and mammalian Tolloid, produce predominantly unprocessed probiglyca n, and MEFs homozygous null for both the Bmp1 gene and the mTLL-1 gene Tll1 produce only unprocessed probiglycan. Thus, all detectable probiglycan-pro cessing activity in MEFs is accounted for by the products of these two gene s.