title: Disruption of Scube2 Impairs Endochondral Bone Formation.
abstract: Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-tethered multidomain SCUBE protein family composed of three members found in vertebrates and mammals. Recent reports suggested that zebrafish scube2 could facilitate sonic hedgehog (Shh) signaling for proper development of slow muscle. However, whether SCUBE2 can regulate the signaling activity of two other hedgehog ligands (Ihh and Dhh), and the developmental relevance of the SCUBE2-induced hedgehog signaling in mammals remain poorly understood. In this study, we first showed that as compared with SCUBE1 or SCUBE3, SCUBE2 is the most potent modulator of IHH signaling in vitro. In addition, gain and loss-of-function studies demonstrated that SCUBE2 exerted an osteogenic function by enhancing Ihh-stimulated osteoblast differentiation in the mouse mesenchymal progenitor cells. Consistent with these in vitro studies and the prominent roles of Ihh in coordinating skeletogenesis, genetic ablation of Scube2 (-/-) caused defective endochondral bone formation and impaired Ihh-mediated chondrocyte differentiation and proliferation as well as osteoblast differentiation of -/- bone-marrow mesenchymal stromal-cell cultures. Our data demonstrate that Scube2 plays a key regulatory role in Ihh-dependent endochondral bone formation.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Yuh-Charn
authors: YC
authors: Lin
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Steve R
authors: SR
authors: Roffler
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Yu-Ting
authors: YT
authors: Yan
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Ruey-Bing
authors: RB
authors: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000473:pathology; D018390:Gene Targeting; D006132:Growth Plate / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D012333:RNA, Messenger; C432427:Scube2 protein, mouse; C514061:ihh protein, mouse; D015675:Osteocalcin; D000469:Alkaline Phosphatase
keywords: BONE μCTCT; GENETIC ANIMAL MODELS; HEDGEHOGS; MOLECULAR PATHWAYS-DEVELOPMENT; OSTEOBLAST