A TGF-β-inducible cell adhesion molecule, βig-h3, is downregulated in melorheostosis and involved in osteogenesis

Melorheostosis is a rare bone disease characterized by linear hyperostosis and associated soft tissue abnormalities. The skin overlying the involved bone lesion is often tense, shiny, erythematous, and scleodermatous. In order to look for genes differentially expressed between the normal and involved skin, we cultured skin fibroblasts from the skin lesions of several afflicted patients, and identified differentially expressed genes by reverse dot-blot hybridization. We found that the genes human TGF-β-induced gene product (βig-h3), osteoblast-specific factor 2, osteonectin, fibronectin, and type I collagen were all downregulated in the affected skin fibroblasts, with βig-h3 the most significantly affected. The expression of βig-h3 was induced by TGF-β in both affected and normal fibroblasts. In an effort to determine the mechanism of bone and skin abnormalities in melorheostosis, we made recombinant βig-h3. Both immobilized and soluble recombinant βig-h3 proteins with or without an RGD motif inhibited bone nodule formation of osteoblasts in vitro. Taken together, our results suggest that altered expression of several adhesion proteins may contribute to the development of hyperostosis and concomitant soft tissue abnormalities of melorheostosis, with βig-h3 in particular playing an important role in osteogenesis. (C) 2000 Wiley-Liss, Inc.