Transforming growth factor-beta activity is potentiated by heparin via dissociation of the transforming growth factor-beta/alpha 2-macroglobulin inactive complex.

Abstract

The control of smooth muscle cell (SMC) proliferation is determined by the combined actions of mitogens, such as platelet-derived growth factor, and the opposing action of growth inhibitory agents, such as heparin and transforming growth factor-beta (TGF-beta). The present studies identify an interaction between heparin and TGF-beta in which heparin potentiates the biological action of TGF-beta. Using a neutralizing antibody to TGF-beta, we observed that the short term antiproliferative effect of heparin depended upon the presence of biologically active TGF-beta. This effect was observed in rat and bovine aortic SMC and in CCL64 cells, but not in human saphenous vein SMC. Binding studies demonstrated that the addition of heparin (100 micrograms/ml) to medium containing 10% plasma-derived serum resulted in a 45% increase in the specific binding of 125I-TGF-beta to cells. Likewise, heparin induced a twofold increase in the growth inhibitory action of TGF-beta at concentrations of TGF-beta near its apparent dissociation constant. Using 125I-labeled TGF-beta, we demonstrated that TGF-beta complexes with the plasma component alpha 2- macroglobulin, but not with fibronectin. Heparin increases the electrophoretic mobility of TGF-beta apparently by freeing TGF-beta from its complex with alpha 2-macroglobulin. Dextran sulfate, another highly charged antiproliferative molecule, but not chondroitin sulfate or dermatan sulfate, similarly modified TGF-beta's mobility. Relatively high, antiproliferative concentrations of heparin (1-100 micrograms/ml) were required to dissociate the TGF-beta/alpha 2-macroglobulin complex. Thus, it appears that the antiproliferative effect of heparin may be partially attributed to its ability to potentiate the biological activity of TGF-beta by dissociating it from alpha 2-macroglobulin, which normally renders it inactive. We suggest that heparin-like agents may be important regulators of TGF-beta's biological activity.

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

“…by preventing the formation of inactive complexes with a2-macroglobulin (15,16). We found that silencing of enzymes that attach sulfate groups to C-6 of glucosamine residues, HS6ST1 and HS6ST2, inhibited TGF-b induction of IL-11.…”

“…It has been shown that TGF-b1 binds to heparin and highly sulfated liver heparan sulfate, and this potentiates the biologic activity of TGF-b1 (15)(16)(17). It is also well established that heparan sulfate-protein interactions critically depend on the amount and the positions of the sulfate groups (18).…”

Expression and matrix deposition of latent transforming growth factor β binding proteins in normal and fibrotic rat liver and transdifferentiating hepatic stellate cells in culture

“…A role of this cell type in the catabolism of bloodborne TGF-␤ has been proposed previously, 52,53 but it is presently not known whether this cytokine circulates in the blood as a component of the large, latent complex, or only bound to ␣ 2 -macroglobulin. [54][55][56] PC, however, could also be relevant for the sequestration of locally produced TGF-␤ complex. Impairment of this mechanism under disease conditions might enhance the half-life time of TGF-␤ (complex) at the site of injury.…”

The extracellular regulation of growth factor action.

“…For example, alpha2-macroglobulin (a2-M) has been found to associate with nerve growth factor (NGF) (Ronne et al, 1979), EGF (Ito et al, 1984), PDGF (Huang et al, 1984) (Borth and Luger, 1989), bFGF (Dennis et al, 1989), IL-6 (Matsuda et al, 1989), and TNF (Wollenberg et al, 1991). Proposed functions for a2-M in regulating growth factor activity include clearance of growth factor from the circulation (LaMarre et al, 1991), inhibition or stimulation of activity (Bonner et al, 1990;Shi et al, 1990), protection from proteolytic degradation (Ronne et al, 1979), and delivery of growth factor to distant sites (McCaffrey et al, 1989).…”