Mechanistic roles of leptin in osteogenic stimulation in thoracic ligament flavum cells.
Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF.
Fan
Dongwei
D
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
Chen
Zhongqiang
Z
Chen
Yupeng
Y
Shang
Yongfeng
Y
D000368:Aged; D000873:Anthracenes / Q000494:pharmacology; D001847:Bone Diseases / Q000175:diagnosis* / Q000473:pathology; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000378:metabolism / Q000502:physiology*; D008023:Ligaments, Articular / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D056920:Nuclear Receptor Coactivator 1; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013896:Thoracic Diseases / Q000175:diagnosis* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
D000873:Anthracenes; D050659:Core Binding Factor Alpha 1 Subunit; D005419:Flavonoids; D020738:Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; C432165:pyrazolanthrone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one