Identification of oxytetracycline as a chondrogenic compound using a cell-based screening system.
To effectively treat degenerative joint diseases including osteoarthritis (OA), small chemical compounds need to be developed that can potently induce chondrogenic differentiation without promoting terminal differentiation. For this purpose, we screened natural and synthetic compound libraries using a Col2GFP-ATDC5 system and identified oxytetracycline (Oxy) as a chondrogenic compound. Oxy induced cartilaginous matrix synthesis and mRNA expressions of chondrocyte markers in ATDC5 cells. In addition, Oxy suppressed mineralization and mRNA expressions of terminal chondrocyte differentiation markers in ATDC5 cells, primary chondrocytes, and cultured metatarsal bones. Oxy's induction of Col2 mRNA expression was decreased by the addition of Noggin and was increased by the addition of BMP2. Furthermore, Oxy increased mRNA expression of Id1, Bmp2, Bmp4, and Bmp6. These data suggest that Oxy induces chondrogenic differentiation in a BMP-dependent manner and suppresses terminal differentiation. Oxy may be useful for treatment of OA and also for regeneration of cartilage tissue.
Hojo
Hironori
H
Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. hojo@bmw.t.u-tokyo.ac.jp
Yano
Fumiko
F
Ohba
Shinsuke
S
Igawa
Kazuyo
K
Nakajima
Keiji
K
Komiyama
Yuske
Y
Kan
Akinori
A
Ikeda
Toshiyuki
T
Yonezawa
Takayuki
T
Woo
Je-Tae
JT
Takato
Tsuyoshi
T
Nakamura
Kozo
K
Kawaguchi
Hiroshi
H
Chung
Ung-il
UI
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D057166:High-Throughput Screening Assays; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008682:Metatarsal Bones / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000188:drug therapy; D010012:Osteogenesis / Q000187:drug effects*; D010118:Oxytetracycline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D054852:Small Molecule Libraries; D046509:Tissue Culture Techniques
D000943:Antigens, Differentiation; D019485:Bone Morphogenetic Proteins; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D010118:Oxytetracycline