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F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-β activation

Mukundan G. Attur^*, Glyn D. Palmer^*, Hayf E. Al-Mussawir^*, Mandar Dave^*, Cristina C. Teixeira, Daniel B. Rifkin, C. Thomas G. Appleton, Frank Beier and Steven B. Abramson^*,1

^* Division of Rheumatology, School of Medicine, Hospital for Joint Diseases,

Department of Basic Science and Craniofacial Biology, College of Dentistry, and

Department of Cell Biology, School of Medicine, New York University, New York, New York, USA; and

CIHR Group in Skeletal Development and Remodeling, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

¹ Correspondence: Division of Rheumatology, New York University School of Medicine, New York University Hospital for Joint Diseases, 301 E. 17th St., New York, NY 10003, USA. E-mail: stevenb.abramson{at}nyumc.org

In osteoarthritis (OA) articular chondrocytes undergo phenotypic changes culminating in the progressive loss of cartilage from the joint surface. The molecular mechanisms underlying these changes are poorly understood. Here we report enhanced (7-fold) expression of F-spondin, a neuronal extracellular matrix glycoprotein, in human OA cartilage (P<0.005). OA-specific up-regulation of F-spondin was also demonstrated in rat knee cartilage following surgical menisectomy. F-spondin treatment of OA cartilage explants caused a 2-fold increase in levels of the active form of TGF-β1 (P<0.01) and a 10-fold induction of PGE2 (P<0.005) in culture supernatants. PGE2 induction was found to be dependent on TGF-β and the thrombospondin domain of the F-spondin molecule. F-spondin addition to cartilage explant cultures also caused a 4-fold increase in collagen degradation (P<0.05) and a modest reduction in proteoglycan synthesis (20%; P<0.05), which were both TGF-β and PGE2 dependent. F-spondin treatment also led to increased secretion and activation of MMP-13 (P<0.05). Together these studies identify F-spondin as a novel protein in OA cartilage, where it may act in situ at lesional areas to activate latent TGF-β and induce cartilage degradation via pathways that involve production of PGE2.—Attur, M. G., Palmer, G. D., Al-Mussawir, H. E., Dave, M., Teixeira, C. C., Rifkin, D. B., Appleton, C. T. G., Beier, F., Abramson, S. B. F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-β activation.

Key Words: extracellular matrix • chondrocyte regulation • prostaglandin