Transforming Growth Factor-β Regulation of Bone Morphogenetic Protein-1/Procollagen C-proteinase and Related Proteins in Fibrogenic Cells and Keratinocytes

Abstract

Transforming growth factor-␤1 (TGF-␤1) induces increased extracellular matrix deposition. Bone morphogenetic protein-1 (BMP-1) also plays key roles in regulating vertebrate matrix deposition; it is the procollagen C-proteinase (PCP) that processes procollagen types I-III, and it may also mediate biosynthetic processing of lysyl oxidase and laminin 5. Here we show that BMP-1 is itself up-regulated by TGF-␤1 and that secreted BMP-1, induced by TGF-␤1, is either processed to an active form or remains as unprocessed proenzyme, in a cell type-dependent manner. In MG-63 osteosacrcoma cells, TGF-␤1 elevated levels of BMP-1 mRNA ϳ7-fold and elevated levels of mRNA for mammalian tolloid (mTld), an alternatively spliced product of the BMP1 gene, to a lesser extent. Induction of RNA was dose-and time-dependent and cycloheximide-inhibitable. Secreted BMP-1 and mTld, induced by TGF-␤1 in MG-63 and other fibrogenic cell cultures, were predominantly in forms in which proregions had been removed to yield activated enzyme. TGF-␤1 treatment also induced procollagen N-proteinase activity in fibrogenic cultures, while expression of the procollagen C-proteinase enhancer (PCPE), a glycoprotein that stimulates PCP activity, was unaffected. In contrast to fibrogenic cells, keratinocytes lacked detectable PCPE under any culture conditions and were induced by TGF-␤1 to secrete BMP-1 and mTld predominantly as unprocessed proenzymes.

Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma

“…At the molecular level, the BMP signal pathway was reported to be critical for calcification and bone formation. 8,[11][12][13]26 The BMP family has at least 30 members, among which BMPs-1-7, which were initially isolated from deminer- alized bone matrix, are capable of inducing ectopic bone formation. 8 BMP-1 is a kind of metalloproteinase with conserved domains, and can convert a variety of precursor proteins into mature or active forms that are involved in extracellular matrix formation.…”

“…8 BMP-1 is a kind of metalloproteinase with conserved domains, and can convert a variety of precursor proteins into mature or active forms that are involved in extracellular matrix formation. 12,13,27,28 It is BMP-1 that converts procollagen types I-III and VII into their mature forms and mediates C-terminal processing of procollagen V homotrimer. 13,27,28 We noted an increased expression of BMP-1 in carcinoma tissues with psammoma bodies or with stromal calcification, which confirms the hypothesized role of BMP-1 in calcification and reveals a possible new role for BMP-1 in the formation of psammoma bodies.…”

“…8 BMP-1 may convert precursor proteins, including laminin-5, procollagen, growth and differentiation factors 8 and 11, and TGF-b1, into their active forms, which play manifold roles in cell adhesion and in regulating mineralization in the extracellular matrix of hard tissue. 8,[10][11][12][13][14][15][16][17] BMP-1 may also activate two other BMP family members, BMP-2 and BMP-4, by cleaving their antagonist, chordin. 11 Therefore, BMP-1 is believed to be an intermediate factor between the TGF-b and BMP signaling pathways.…”

Profiling of genes which are differentially expressed in mouse liver in response to adenoviral vectors and delivered genes

“…Bone morphogenetic protein (BMP-1) is identical to procollagen C-proteinase, which cleaves the COOH-propeptides of procollagens I, II and III to yield to major fibrous components of vertebrate extracellular matrix. 21,22 CTGF and TGF␤1 are known to increase the collagen deposition of at least type I and type III collagen. The induction of proteinase C in liver tissue by overexpression of CTGF and TGF␤1 provides a possible explanation for the increase in collagen type I and III.…”

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

“…Although LTBP1 cleavage by BMP1/TLD-like proteinases does not directly activate TGFβ1, it does appear to liberate LLCs from the ECM, thereby rendering LAP susceptible to cleavage by MMP2, and possibly by MMPs 9 and 14, with consequent TGFβ1 activation . TGFβ1 activation by BMP1/TLD-like proteinases, MMP2, and potentially MMP9, all of which are potently up-regulated by TGFβ1 (Brown et al, 1990;Lee et al, 1997;Marti et al, 1994;Overall et al, 1991;Sehgal and Thompson, 1999) suggests a fast-forward loop of potential importance to tissue remodeling (Fig. 6).…”