Sanja Zoričić Cvek

BMP signaling in rats with TNBS-induced colitis following BMP7 therapy.

Beyond stimulating bone formation, bone morphogenetic proteins (BMPs) are important in development, inflammation, and malignancy of the gut. We have previously shown that BMP7 has a regenerative, anti-inflammatory, and antiproliferative effect on experimental inflammatory bowel disease (IBD) in rats. To further investigate the BMP signaling pathway we monitored the effect of BMP7 therapy on the BMP signaling components in the rat colon during different stages of experimentally induced colitis by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed a significantly decreased BMP7 expression in the acute phase, followed by a significantly increased BMP2 and decreased BMP6 expression during the chronic phase of colitis. BMP7 therapy influenced the expression of several BMPs with the most prominent effect on downregulation of BMP2 and upregulation of BMP4 in the chronic phase of colitis. Importantly, connective tissue growth factor and noggin expression were elevated in the acute stage and significantly decreased upon BMP7 therapy. BMP receptor I expression was unchanged, whereas BMP receptor II was decreased at day 2 and increased at days 14 and 30 of TNBS inflammation. However, an opposite pattern of expression following BMP7 therapy has been observed. BMP7 increased the expression of BR-Smad including Smad3 and Smad4. Inhibitory Smads were increased in colitis and significantly decreased following BMP7 therapy at later stages of the disease. We suggest that BMP signaling was altered during TNBS-induced colitis and was recovered with BMP7 administration, suggesting that IBD is a reversible process.

Hepatoregenerative role of bone morphogenetic protein-9

Summary Bone morphogenetic protein-9 (BMP-9) is a member of the transforming growth factor beta (TGF-β) superfamily of cytokines, which regulate cell growth and differentiation during embryogenesis. Apart of that, the hypoglycemic potential of BMP-9 is of great interest. It has been confirmed that BMP-9, like insulin, improves glycemia in diabetic mice and regulates directional glucose metabolism in hepatocytes; therefore it is proposed to be a candidate hepatic insulin-sensitizing substance (HISS). In liver fibrosis, due to the portocaval shunt, insulin bypasses the organ and the liver undergoes atrophy. Parenteral administration of insulin reverses atrophy by stimulating mitogenic activity of the hepatocytes. Because BMP-9 has a signaling pathway similar to other BMPs and insulin, it is to be expected that BMP-9 has a certain regenerative role in the liver, supporting the above-mentioned is evidence of BMP-9 expression in Dissè’s spaces and BMP-7’s mitogenic activity in mucosal cells. However, further studies are needed to confirm the possible regenerative role of BMP-9.

Correlation of endothelin-1 mRNA expression and bone structure in advanced osteoarthritis

Recent understandings of the vascular contribution of pathophysiology of osteoarthritis (OA) mount new evidence of cross-talking between subchondral bone tissue and articular cartilage that might have a decisive role in a pathophysiology of Osteoarthritis (OA). These understandings include blood flow (or interstitial fluid) impairment in subchondral bone. With regard to the mentioned role of the vasculature, the absence of custom nourishing to articular cartilage, and established, vasoconstrictive role of endothelin-1 (ET-1) it was reasonable to assume that ET-1 has an inconvertible role in pathophysiology of OA. Another moment in pathophysiology of OA is apoptosis of subchondral osteocytes, what induces osteoclastic resorption and at least temporarily reduces the bony support for the overlying cartilage. Since regional dependence of this proteins expression was presumed, we suggest a regional division of subchondral bone by histomorphometrical analysis and quantification of identified protein by Real Time Polymerase Chain Reaction Analysis (RT-PCR). Obtained results should be compared to serum levels of soluble ET-1, what would enforce this methods validity. Herewith, a new screening marker of patients with osteoarthritis would be established. This would enable detection and follow-up of groups threatened by this, growing, cause of disability and decreased quality of life.