ADAM-12 (meltrin alpha) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage
| Autor: | Takayuki Shiomi, Atsuko Sehara-Fujisawa, Yoshinari Fujita, Yasunori Okada, Aiko Okada, Satsuki Mochizuki, Yukihide Iwamoto, Taku Yatabe, Tokuhiro Kimura, Hideo Matsumoto |
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| Rok vydání: | 2008 |
| Předmět: |
Cartilage
Articular Small interfering RNA medicine.medical_treatment Immunology ADAM12 Protein In situ hybridization Chondrocyte Insulin-like growth factor-binding protein Chondrocytes Rheumatology Transforming Growth Factor beta medicine Immunology and Allergy Humans Pharmacology (medical) RNA Messenger Insulin-Like Growth Factor I Growth Substances Cells Cultured Aged Cell Proliferation Aged 80 and over biology Chemistry Growth factor Cartilage Binding protein Membrane Proteins Osteoarthritis Knee Cell biology carbohydrates (lipids) ADAM Proteins medicine.anatomical_structure Case-Control Studies biology.protein Cytokines Insulin-Like Growth Factor Binding Protein 5 Transforming growth factor |
| Zdroj: | Arthritis and rheumatism. 58(3) |
| ISSN: | 0004-3591 |
| Popis: | Objective ADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up-regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function. Methods Expression of the 13 different metalloproteinase-type ADAMs was screened by reverse transcription–polymerase chain reaction (PCR), and expression levels of prototype membrane-anchored ADAM-12 (ADAM-12m) were determined by real-time PCR. ADAM-12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM-12m. Results ADAM-12m was selectively expressed in 87% of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM-12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM-12m. ADAM-12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin-like growth factor binding protein 5 (IGFBP-5). TGFβ-induced chondrocyte proliferation was inhibited by suppression of IGF-1 signaling. In addition, TGFβ-induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP-5 were inhibited with ADAM inhibitor, anti–ADAM-12 antibody, and small interfering RNA for ADAM-12. Conclusion These data suggest a novel function of ADAM-12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF-1 from the IGF-1–IGFBP-5 complex by selective IGFBP-5 digestion. |
| Databáze: | OpenAIRE |
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