Regulation Of TGF-beta Activity Research Articles

Enhanced SDF-1 and rantes attract the locally injected bone marrow stromal cells to remedy dental biomechanically induced temporomandibular joint osteoarthritic lesions

Enhanced SDF-1 and rantes attract the locally injected bone marrow stromal cells to remedy dental biomechanically induced temporomandibular joint osteoarthritic lesions

Integrin αvβ8-Mediated Activation of Transforming Growth Factor-β by Perivascular Astrocytes: An Angiogenic Control Switch

Brain hemorrhage is a severe complication of both neoplastic and nonneoplastic brain disease. Mice deficient in the alpha(v)beta8 integrin display defective brain vessel formation resulting in hemorrhage and perinatal death, but the mechanism of brain hemorrhage is unknown. Because the alpha(v)beta8 integrin is expressed by astrocytes and not expressed by endothelium, paracrine interactions between astrocytes and endothelial cells could contribute to the maintenance of brain vessel integrity. We have investigated the mechanisms underlying astrocytic-endothelial paracrine signaling and have found that integrin-mediated activation of transforming growth factor (TGF)-beta by astrocytes influences endothelial cell function. Thus, we identified the integrin alpha(v)beta8 in human perivascular glial cell processes surrounding developing blood vessels. Human astrocytic alpha(v)beta8 was a major cell surface receptor for latent TGF-beta, and alpha(v)beta8-dependent activation of TGF-beta was the major mechanism of TGF-beta activation in primary cultures of astrocytes or freshly dissociated fetal brain cells. This activation of TGF-beta was sufficient to inhibit endothelial migration in fibrin gels and to alter expression of genes affecting proteolytic and angiogenic pathways. Taken together, our data suggest that astrocytic alpha(v)beta8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-beta activation and expression of TGF-beta-responsive genes that promote vessel differentiation and stabilization, most notably plasminogen activator inhibitor-1 and thrombospondin-1.

Thrombospondin 1 does not activate transforming growth factor β1 in a chemically defined system or in smooth-muscle-cell cultures

The cytokine transforming growth factor beta1 (TGF-beta1) is secreted in a latent form that has no known biological activity. The conversion of latent TGF-beta1 into its biologically active 25 kDa form is thought to be an important step in the regulation of TGF-beta activity both in cell culture and in vivo. Thrombospondin (TSP)-1, a 360 kDa platelet alpha-granule and extracellular matrix protein, has been shown to participate in TGF-beta1 activation. We have used a chemically defined system to examine the mechanism of TSP-1-mediated TGF-beta1 activation. However, the addition of two different preparations of TSP-1 to recombinant small latent TGF-beta1 in the test tube resulted in only a very small increase in the proportion of the TGF-beta1 able to bind to the TGF-beta type II receptor: from 0.1% to a maximum of 0.4%. This small effect was not specific for TSP-1: matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinase 2 and active plasminogen activator inhibitor 1, but not transglutaminase, human serum albumin or immunoglobulin, had quantitatively similar effects on latent TGF-beta1. Furthermore, no change in the activity associated with small latent TGF-beta1 was noted in either mink lung epithelial cell or rat aortic smooth-muscle cell culture systems in the presence of TSP-1 (or TSP-1-derived peptides). We conclude that TSP-1, either alone or in the presence of cultured smooth-muscle cells (a cell type known to activate latent TGF-beta in vitro and in vivo) is unable to activate latent TGF-beta1. Any TSP-mediated activation of TGF-beta1 must depend on additional factor(s) not present in our systems.

Effects of retinol on activation of latent transforming growth factor-beta by isolated osteoclasts.

The multifunctional cytokine, transforming growth factor-beta (TGF beta), is found in many tissues in a latent or inactive form. The nature and composition of the latent complex can vary depending on tissue type. The release of active TGF beta from its latent complex is a potentially important mechanism for regulation of TGF beta activity. We have shown previously that osteoclasts activate latent TGF beta produced by bone and that bone cells produce a 100-kDa latent complex that lacks the latent TGF beta-binding protein. Here we investigated the effects of retinol on osteoclast activation of various forms of latent TGF beta. Two sources of osteoclasts were used that provide either mature avian osteoclasts or avian osteoclast precursors. Whereas both cell populations activate latent TGF beta, only mature osteoclasts respond to retinol with an increase in activation of latent TGF beta over basal levels. Activation could not be ascribed to pH changes in conditioned medium. Nonacid-dissociable 100-kDa latent complex, which is also produced by bone cells, was added to mature osteoclasts and to osteoclast precursors, but no activation was observed. Platelet latent TGF beta, which contains the 130-kDa latent TGF beta-binding protein, was activated by both osteoclast populations. Conditioned medium from the precursor population activated latent complex, whereas conditioned medium from mature cells did not. Activation of latent TGF beta by retinol-treated mature cells was not blocked by inhibitors of plasmin, nor was activation by conditioned medium from precursor cells. These data suggest that retinol-induced activation of latent TGF beta by osteoclasts is dependent on the stage of differentiation of these cells and the presence of other cell types, and that unlike other cell systems, the plasmin-plasminogen activator mechanism is not involved.

Glucocorticoid regulation of transforming growth factor-beta activation in urogenital sinus mesenchymal cells.

The transforming growth factors-beta (TGF-beta s) regulate many aspects of cell proliferation and differentiation. The TGF-beta isoforms are produced by most cell types in the biologically inactive, latent form. The physiological relevance of latent TGF-beta and the regulation of activation to the biologically active form are not well understood. Although expression of TGF-beta messenger RNA is regulated by the steroid hormone family, the mechanisms of hormonal regulation of TGF-beta activation have not been well studied. Fetal rat urogenital sinus organ cultures and derived mesenchymal cell lines (U4F, U4F1) have been established in order to analyze the expression of growth and differentiation regulatory factors which may function in mesenchymal induction of epithelial differentiation. The U4F1 cell line in chemically defined medium upon supplementation with dexamethasone (10 nM-1.4 microM), produced an activity which was growth inhibitory to PC-3 prostatic carcinoma epithelial cells. Analysis of physicochemical properties and purification of activity demonstrated a 25-kDa protein was responsible for activity. The activity cross-reacted to antisera specific for TGF-beta 1, beta 2 and for TGF-beta 2 exclusively, but not with antisera to rat interferon (alpha-beta) or rat interleukin 6. Acid treatment of control (unsupplemented) conditioned medium and cultures supplemented with other steroid hormones produced identical levels of activated TGF-beta as nonacid-treated conditioned medium from dexamethasone supplemented cultures which did not increase levels of activity upon acid activation. Activity from the acid-treated control conditioned medium was neutralized by TGF-beta antibodies. These data suggest latent TGF-beta is produced constitutively by U4F1 mesenchymal cultures in steroid unsupplemented medium and these cultures are induced by dexamethasone to activate identical levels of TGF-beta. These observations may be relevant to understanding diverse aspects of glucocorticoid regulation of tissue function and suggests that TGF-beta may be relevant to paracrine and autocrine growth regulation in the developing urogenital sinus.