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Osteoactivin Stimulates MMP-3 Expression of Fibroblasts Infiltrated into Denervated Skeletal Muscle in Mice   H. Furouchi, T. Ogawa, K. Hirasaka, N. Suzue, K. Sairyo, N. Yasui, K. Kishi, T. Nikawa.  The University of Tokushima School of Medicine, Tokushima, Japan

There are also several evidences that denervation (sciatic neurectomy) alters interstitial spaces between muscle fibers: mononucleated cells were infiltrated into interstitial spaces of muscle fibers, and fibrosis occasionally occurs in the muscle.  However, information on the interaction between muscle fiber membrane and infiltrated cells are quite little.  To address this issue, we previously examined the expression of about 26,000 genes in gastrocnemius muscle atrophied by denervation or spaceflight by using an Affymetrix DNA microarray analytical system.  We found that both muscle atrophic conditions remarkably increased the expression of osteoactivin, a type I membrane glycoprotein, in skeletal muscle.  Osteoactivin is a rat homologue of Gpnmb family, which is originally reported to be highly expressed in human melanoma cells.  In this study, we examined a pathophysiological role of osteoactivin in skeletal muscle atrophied by denervation.  Osteoactivin did not induce MMP-3 expression in myoblastic cells, whereas it clearly upregulated expression of MMP-3 in fibroblasts.  Furthermore, immunohistochemical analysis revealed the distinct localization between MMP-3 and osteoactivin in denervated skeletal muscle.  These results suggest that osteoactivin functions as an activator for fibroblasts.  This hypothetical function of osteoactivin is consistent with the previous findings that osteoactivin is preferentially induced in various diseases occurring fibrosis, such as osteopetrosis and liver cirrhosis.  Our present results provide a novel target for the development of therapeutic strategies for fibrosis, an irreversible degeneration.

(Supported by the Sasakawa Scientific Research Grant from the Japan Science Society)