Stimulation of chondrogenesis in ATDC5 chondroprogenitor cells and hypertrophy in mouse by Genkwadaphnin.
The growth in height of the bone plate is a result of endochondral proliferation in epiphyseal growth plates and the conversion of chondrocytes into new bone. The control of chondrogenic differentiation and hypertrophy is critical for these processes. The present study was aimed to demonstrate the chondromodulating activity of Genkwadaphnin. ATDC5 cultures treated with Genkwadaphnin produced cartilaginous nodules that were greater in number and larger in size than control cultures. Genkwadaphnin treated ATDC5 cells also stained more intensely with Alcian blue than control cells, suggesting greater synthesis of matrix proteoglycans in the former. Genkwadaphnin markedly induced the activation of alkaline phosphatase, as well as the expression of chondrogenic marker genes such as type II collagen, aggrecan, type I collagen, type X collagen, osteocalcin, and bone sialoprotein in ATDC5 cells. The expression of signaling molecules involved in chondrogenesis including Smad4, Sox9, and β-catenin was also induced by treatment of ATDC5 cells with Genkwadaphnin. Furthermore, Genkwadaphnin induced the activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). To analyze the role of Genkwadaphnin in growth plate chondrocyte in vivo, we analyzed chondrogenesis in mice treated with Genkwadaphnin. The significant expansion in growth plate and hypertrophic zone and numerous numbers of chondrocyte positive cells in hypertrophic and proliferative bone areas were observed. These observations provide the first evidence that Genkwadaphnin has chondromodulating activity and may open new therapeutic avenues to treat a variety of skeletal diseases, such as dwarfism.
Department of Dental Pharmacology, School of Dentistry, and Brain Korea 21 Project, Chonbuk National University, Jeon-Ju 561-756, Republic of Korea.
Hwa Jung
HJ
Choi
Manoj
M
Nepal
Young-Ran
YR
Park
Hyeong-Kyu
HK
Lee
Sei-Ryang
SR
Oh
Yunjo
Y
Soh
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001847:Bone Diseases / Q000188:drug therapy; D002356:Cartilage / Q000187:drug effects / Q000254:growth & development; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D020219:Chondrogenesis / Q000187:drug effects* / Q000235:genetics; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects; D006984:Hypertrophy / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D013977:Tibia / Q000166:cytology / Q000187:drug effects / Q000254:growth & development
D015415:Biomarkers; D004224:Diterpenes; D011509:Proteoglycans; C036412:genkwadaphnin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase