title: Insulin-like growth factor-1 and bone morphogenetic protein-2 jointly mediate prostaglandin E2-induced adipogenic differentiation of rat tendon stem cells.
abstract: Tendinopathy is characterized histopathologically by lipid accumulation and tissue calcification. Adipogenic and osteogenic differentiation of tendon stem cells (TSCs) are believed to play key roles in these processes. The major inflammatory mediator prostaglandin E2 (PGE2) has been shown to induce osteogenic differentiation of TSCs via bone morphogenetic protein-2 (BMP-2), and BMP-2 has also been implicated in adipogenic differentiation of stem cells. We therefore examined the mechanisms responsible for PGE2-induced adipogenesis in rat TSCs in vitro. Insulin-like growth factor-1 (IGF-1) mRNA and protein were significantly up-regulated in PGE2-stimulated TSCs, measured by quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Incubation with specific inhibitors of cAMP, cAMP-dependent protein kinase A (PKA), and CCAAT/enhancer binding protein-δ (CEBPδ) demonstrated that IGF-1 up-regulation occurred via a cAMP/PKA/CEBPδ pathway. Furthermore, neither IGF-1 nor BMP-2 alone was able to mediate adipogenic differentiation of TSCs, but IGF-1 together with BMP-2 significantly increased adipogenesis, indicated by Oil Red O staining. Moreover, knock-down of endogenous IGF-1 and BMP2 abolished PGE2-induced adipogenic differentiation. Phosphorylation of CREB and Smad by IGF-1 and BMP-2, respectively, were required for induction of the adipogenesis-related peroxisome proliferator-activated receptor γ2 (PPARγ2) gene and for adipogenic differentiation. In conclusion, IGF-1 and BMP-2 together mediate PGE2-induced adipogenic differentiation of TSCs in vitro via a CREB- and Smad-dependent mechanism. This improved understanding of the mechanisms responsible for tendinopathies may help the development of more effective therapies.
authors.affiliation: Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Junpeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Wuhan General Hospital of Guangzhou Military Region, Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: You
authors.initials: Y
authors.lastname: zhou
authors.affiliation: Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiangzhou
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Kanglai
authors.initials: K
authors.lastname: Tang
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013710:Tendons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; C497254:Cebpd protein, rat; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; C548904:insulin-like growth factor-1, rat; D051743:CCAAT-Enhancer-Binding Protein-delta; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone