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Thyroid Hormone Enhances Aggrecanase-2/ADAM-TS5 Expression and Proteoglycan Degradation in Growth Plate Cartilage

Departments of Prosthetic Dentistry (S.M., M.F., H.N., T.H.) and Biochemistry (W.Y., E.Y., Y.K.), Hiroshima University Faculty of Dentistry, Minami-ku, Hiroshima 734-8553, Japan; Department of Pediatrics, Osaka City University Medical School (H.M.), Abeno-ku, Osaka 545-8585, Japan; Department of Immunology, The Forsyth Institute (S.M., T.K.), Boston, Massachusetts 02115; and Department of Pathology, Keio University School of Medicine (Y.O.), Shinjuku-ku, Tokyo 160-8582, Japan

Address all correspondence and requests for reprints to: Dr. Seicho Makihira, Department of Immunology, The Forsyth Institute, 140 Fenway, Boston, Massachusetts 02115. E-mail: smakihira{at}forsyth.org.

Effects of thyroid hormone on proteoglycan degradation in various regions of cartilage were investigated. In propylthiouracil-treated rats with hypothyroidism, proteoglycan degradation in epiphyseal cartilage during endochondral ossification was markedly suppressed. However, injections of T₄ reversed this effect of propylthiouracil on proteoglycan degradation. In pig growth plate explants, T₃ also induced breakdown of proteoglycan. T₃ increased the release of aggrecan monomer and core protein from the explants into the medium. Accordingly, the level of aggrecan monomer remaining in the tissue decreased after T₃ treatment, and the monomer lost hyaluronic acid-binding capacity, suggesting that the cleavage site is in the interglobular domain. The aggrecan fragment released from the T₃-exposed explants underwent cleavage at Glu³⁷³-Ala³⁷⁴, the major aggrecanase-cleavage site. The stimulation of proteoglycan degradation by T₃ was less prominent in resting cartilage explants than in growth plate explants and was barely detectable in articular cartilage explants. Using rabbit growth plate chondrocyte cultures, we explored proteases that may be involved in T₃-induced aggrecan degradation and found that T₃ enhanced the expression of aggrecanase-2/ADAM-TS5 (a disintegrin and a metalloproteinase domain with thrombospondin type I domains) mRNA, whereas we could not detect any enhancement of stromelysin, gelatinase, or collagenase activities or any aggrecanase-1/ADAM-TS4 mRNA expression. We also found that the aggrecanse-2 mRNA level, but not aggrecanase-1, increased at the hypertrophic stage during endochondral ossification. These findings suggest that aggrecanse-2/ADAM-TS5 is involved in aggrecan breakdown during endochondral ossification, and that thyroid hormone stimulates the aggrecan breakdown partly via the enhancement of aggrecanase-2/ADAM-TS5.

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