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Cathepsin S Promotes Human Preadipocyte Differentiation: Possible Involvement of Fibronectin Degradation

Institut National de la Santé et de la Recherche Médicale (S.T., R.C., K.C., D.L.), Unité 755 Nutriomique, University Pierre and Marie Curie-Paris 6 (S.T., R.C., K.C., D.L.), Faculty of Medicine Les Cordeliers, and Assistance Publique-Hôpitaux de Paris (K.C.), Hôtel-Dieu Hospital, Department of Nutrition, 75004 Paris, France

Address all correspondence and requests for reprints to: Professor Karine Clément or Dr. Danièle Lacasa, Institut National de la Santé et de la Recherche Médicale, Unité 755, Department of Nutrition, Hôtel-Dieu, Place du parvis Notre-Dame, 75004 Paris, France. E-mail: karine.clement{at}htd.aphp.fr or daniele.lacasa{at}ea3502.org.

We previously showed that the cysteine protease cathepsin S (CTSS), known to degrade several components of the extracellular matrix (ECM), is produced by human adipose cells and increased in obesity. Because ECM remodeling is a key process associated with adipogenesis, this prompted us to assess the potential role of CTSS to promote preadipocyte differentiation. Kinetic studies in primary human preadipocytes revealed a modest increase in CTSS gene expression and secretion at the end of differentiation. CTSS activity was maximal in preadipocyte culture medium but decreased thereafter, fitting with increased release of the CTSS endogenous inhibitor, cystatin C, during differentiation. Inhibition of CTSS activity by an exogenous-specific inhibitor added along the differentiation, resulted in a 2-fold reduction of lipid content and expression of adipocyte markers in differentiated cells. Conversely, the treatment of preadipocytes with human recombinant CTSS increased adipogenesis. Moreover, CTSS supplementation in preadipocyte media markedly reduced the fibronectin network, a key preadipocyte-ECM component, the decrease of which is required for adipogenesis. Using immunohistochemistry on serial sections of adipose tissue of obese subjects, we showed that adipose cells staining positive for CTSS are mainly located in the vicinity of fibrosis regions containing fibronectin. Herein we propose that CTSS may promote human adipogenesis, at least in part, by degrading fibronectin in the early steps of differentiation. Taken together, these results indicate that CTSS released locally by preadipocytes promotes adipogenesis, suggesting a possible contribution of this protease to fat mass expansion in obesity.

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