Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves' Orbitopathy

PURPOSE. We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-beta superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The ther-apeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.METHODS. Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-beta, IL-1 beta, and TNF-alpha. Fibrosis-related proteins and inflamma-tory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.RESULTS. The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1 alpha, and alpha-SMA induced by TGF-beta were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-beta induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1 beta or TNF-alpha were blocked by rhBMP7 treatment, and the expression of phosphorylated NF Kappa B and Akt was suppressed by rhBMP7 treatment.CONCLUSIONS. BMP7 transcript levels were downregulated in Graves' orbital tissues. Exoge-nous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-beta/SMAD signaling and proinflammatory cytokine production.