Molecules associated with TGF-β superfamily such as BMPs and TGF-β are key regulators of inflammation, apoptosis and cellular transitions. Here, we demonstrate that the BMP receptor activin–like kinase 3 (Alk3) is elevated early in response to kidney injury and its deletion in the tubular epithelium leads to enhanced TGF-β1 / Smad3 signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3 mediated signaling. Structure–function analysis of Alk3 / BMP / BMPRII ligand–receptor complex coupled with synthetic organic chemistry led us to construct a library of small peptide agonists of BMP signaling that function via Alk3 receptor. One such peptide agonist, THR–123, suppressed inflammation, apoptosis epithelial–to–mesenchymal transition program, and reversed fibrosis in mouse models of acute and chronic injury. Combining THR–123 and angiotensin–converting enzyme inhibitor, captopril, exhibited additive therapeutic benefit in controlling fibrosis. Our studies demonstrate that BMP signaling agonists constitute a new line of therapeutic agents with a potential utility in the clinic to induce regeneration, repair and reverse fibrosis.
Bone morphogenetic protein-7 (BMP-7) is a growth and differentiation factor and belongs to the TGF-beta superfamily of proteins. Previous studies have shown an abundant expression of BMP-7 in the developing intestine and an association with a perturbed BMP/SMAD downstream signaling leading to a malignant phenotype and inflammation in the gut. In the present study, we have evaluated the effect of systemically administered recombinant human BMP-7 against trinitrobenzenesulfonic (TNBS) acid induced inflammatory bowel disease (IBD) in rats. The TNBS administered rats treated with BMP-7 have developed much less severe form of colitis based on macroscopic and histological scoring when administered 1.5 h before or 24 h after colitis induction. Bioavailability studies in healthy rats have revealed that significant portion (3.6%) of i.v. administered BMP-7 is targeted for BMP-7 receptors in the stomach and ileum, respectively, suggesting its availability to target tissue upon administration. Immunohistochemical and RT-PCR analyses have shown elevated expression of pro-inflammatory (IL-6, TNF-beta, ICAM-1) and pro-fibrogenic (TGF-beta) cytokines, and BMP-7 treatment significantly reduced their expression in the intestine; among which the suppression of IL-6 appeared to be the most important. Taken together, the results of this study suggest that BMP-7 plays an important role in the regulation of anti-inflammatory response in the adult gut tissue.
We demonstrated, to our knowledge for the first time, the presence of membrane-bound, specific, high-affinity OP-1 receptors in rat kidney tissues, which are likely to mediate OP-1 actions in the kidney. The major OP-1-binding component of the kidney appears to be a long form of BMP type II receptor with a Mr of 100 kD. In vivo and in vitro evidence suggests that the cellular targets for OP-1 are convoluted tubule epithelium, glomeruli, and collecting ducts. OP-1 does not share receptor binding properties with other growth factors, including BMP-2 and CDMP-1, suggesting that its mode of action in kidney appears to be specific.
The follicle-stimulating hormone (FSH) receptor purified from calf bovine testis membranes appears to be an oligomeric glycoprotein, consisting of 4 disulfide-linked monomers of molecular weight about 60,000 each. Polyclonal antibodies to the hormone binding sites of the receptor have been developed. FSH interaction with the receptor seems to involve multiple discrete binding regions, which include amino acids 34-37 and 49-52 of the human FSH beta subunit. The interaction between FSH and the membrane-bound receptor is reversible at low temperatures but becomes increasingly irreversible as the temperature increases. FSH interaction with the soluble receptor is reversible over a wider temperature range. The hydrophobic effect is a significant factor in the initial hormone receptor interaction in each system. FSH bound to membrane receptors on cultured immature rat Sertoli cells is internalized and degraded to the level of amino acids. Current evidence suggests that the membrane receptor may exist as free receptor, and complexed with G-protein. A functional receptor/G-protein/adenylate cyclase complex has been reconstituted in liposomes. The G-protein of testis membranes contains both high and low affinity guanosine triphosphate (GTP) binding sites. Both are capable of modulating FSH receptor binding, whereas only the high affinity sites seem to be required for activation of adenylate cyclase. Although testis membranes contain a phosphatidylinositide hydrolysis system, the latter is not directly influenced by FSH.
We have previously shown that hFSH-beta 34-37 (KTCT) and 49-52 (TRDL) inhibit binding of 125I-hFSH to FSH receptor in calf testis membranes and that hFSH-beta 33-53, which encompasses these tetrapeptides, inhibits binding with increased potency. hFSH-beta 33-53 rapidly dimerizes under conditions utilized in the receptor binding assay (pH 7.5) so that the binding inhibition reported earlier was due to the hFSH-beta 33-53 dimer rather than the monomer. At pH 6.5, conversion to dimer does not occur, and binding inhibition could be unequivocally attributed to the monomer. Radioiodinated and alkylated hFSH-beta 33-53 binds to the FSH receptor with a Kd = (5.5 +/- 1.4) X 10(-5) M. The biological activity of hFSH-beta 33-53 was assessed by its ability to affect the conversion of androstenedione to estradiol in rat Sertoli cells cultures. FSH-beta 33-53 behaved as a partial antagonist of the FSH-induced estradiol synthesis. The required incubation medium, however, contains cystine as well as cystine, which rapidly forms a hFSH-beta Cys-(51)-S-S-Cys derivative at the pH of the incubation, 7.4. When hFSH-beta 33-53 was converted either to the hFSH-beta Cys(51)-S-S-Cys or to a carboxymethylated derivative, inhibition of FSH-induced estradiol synthesis still was observed. This result demonstrates that the free R-SH group at Cys51 is not responsible for the inhibition. FSH-beta 33-53 also significantly stimulated basal levels of estradiol synthesis, but not to maximal levels observed with FSH (partial agonist). Neither the carbohydrate content of hFSH-beta nor the alpha subunit of FSH appears to be essential for signal transduction and expression of the hormone effect of FSH-beta 33-53.
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