title: Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation.
abstract: Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss-of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-β1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-β/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jirong R
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: Chaojun J
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Chengyun Y
authors.initials: CY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaokai K
authors.initials: XK
authors.lastname: Wu
authors.affiliation: Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
authors.forename: Dun
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Orthopedics, Taizhou Hospital, Linhai 317000, China.
authors.forename: Haixiao X
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Departments of Orthopaedic Surgery, Medicine and Developmental Biology, Washington University, St. Louis, Missouri 63110.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China Departments of Orthopaedic Surgery, Medicine and Developmental Biology, Washington University, St. Louis, Missouri 63110 xiwu@zju.edu.cn.
authors.forename: Ximei M
authors.initials: XM
authors.lastname: Wu
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis; D055758:SOX9 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D055396:Bone Morphogenetic Protein 2; C581598:Cdc42 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016212:Transforming Growth Factor beta; D020764:cdc42 GTP-Binding Protein
keywords: Cdc42; chondrocyte; condensation; osteoblast