Proteolysis of Latent Transforming Growth Factor-β (TGF-β)-binding Protein-1 by Osteoclasts

Abstract

The binding of growth factors to the extracellular matrix (ECM) may be a key pathway for regulation of their activity. We have shown that a major mechanism for storage of transforming growth factor-␤ (TGF-␤) in bone ECM is via its association with latent TGF-␤-binding protein-1 (LTBP1). Although proteolytic cleavage of LTBP1 has been reported, it remains unclear whether this represents a physiological mechanism for release of matrix-bound TGF-␤. Here we examined the role of LTBP1 in cell-mediated release of TGF-␤ from bone ECM. We first characterized the soluble and ECM-bound forms of latent TGF-␤ produced by primary osteoblasts. Next, we examined release of ECM-bound TGF-␤ by bone resorbing cells. Isolated avian osteoclasts and rabbit bone marrow-derived osteoclasts released bone matrixbound TGF-␤ via LTBP1 cleavage. 1,25-Dihydroxyvitamin D 3 enhanced LTBP1 cleavage, resulting in release of 90% of the ECM-bound LTBP1. In contrast, osteoblasts failed to cleave LTBP1 or release TGF-␤ from bone ECM. Cleavage of LTBP1 by avian osteoclasts was inhibited by serine protease and metalloproteinase (MMP) inhibitors. Studies using purified proteases showed that plasmin, elastase, MMP2, and MMP9 were able to cleave LTBP1 to produce 125-165-kDa fragments. These studies identify LTBP1 as a novel substrate for MMPs and provide the first demonstration that LTBP1 proteolysis may be a physiological mechanism for release of TGF-␤ from ECM-bound stores, potentially the first step in the pathway by which matrix-bound TGF-␤ is rendered active.

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

“…Current data suggest that proteolytic release of ECM-bound LTBPs may represent a major mechanism for the activation of TGF-b under physiological conditions. 24,46 Our data are further suggestive of two sources for activation of TGF-b during apoptosis of HUVECs: the secretion of intracellular TGF-b from apoptotic cells and the proteolytic release of stored LL-TGF-b from the ECM. Both of these sources appear to be utilized during apoptosis of HUVECs, as in the anoikis model of apoptosis the activation of TGF-b can be observed despite the lack of endogenous ECM ( Figure 5).…”

Mechanisms of multiple myeloma bone disease

“…18 -20 Finally, the bone resorption process releases immobilized growth factors, such as transforming growth factor-(TGF ), from the bone matrix, which also drive tumor growth. 21 This ' vicious cycle ' of bone destruction whereby myeloma cells drive bone destruction, which in turn increases tumor growth, highlights the critical role that bone disease has in myeloma. All active multiple myeloma patients progress from monoclonal gammopathy of unknown Mechanisms of multiple myeloma bone disease DL Galson et al significance, a premalignant plasma cell disorder without osteolytic lesions.…”

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…For example, degradation of laminin-5 (Ln-5) by MMP-2 results in the exposure of a Ln-5 cryptic site that enhances endothelial cell migration [2,92,96,97]. Besides degradation of ECM, MMPs are also capable of releasing growth factors from ECM and/or inactive complexes, cleaving growth factor receptors and activating growth factors excreted as pre-pro-enzymes, like transforming growth factor (TGF)-␣, TGF-␤, macrophage-colony stimulating factor (M-CSF), insulin like growth factor (IGF) and fibroblast growth factor receptor (FGFR)-1 [4,98,[98][99][100][101][102][103][104][105][106][107][108][109]. As pointed out, above MMPs can directly or indirectly induce tumor angiogenesis through degradation of ECM and release or activation of growth factors, like TNF-␣ and TGF-␤.…”