Sonic Hedgehog Promotes Cementoblastic Differentiation via Activating the BMP Pathways
- 553 Downloads
Although sonic hedgehog (SHH), an essential molecule in embryogenesis and organogenesis, stimulates proliferation of human periodontal ligament (PDL) stem cells, the effects of recombinant human SHH (rh-SHH) on osteoblastic differentiation are unclear. To reveal the role of SHH in periodontal regeneration, expression of SHH in mouse periodontal tissues and its effects on the osteoblastic/cementoblastic differentiation in human cementoblasts were investigated. SHH is immunolocalized to differentiating cementoblasts, PDL cells, and osteoblasts of the developing mouse periodontium. Addition of rh-SHH increased cell growth, ALP activity, and mineralization nodule formation, and upregulated mRNA expression of osteoblastic and cementoblastic markers. The osteoblastic/cementoblastic differentiation of rh-SHH was abolished by the SHH inhibitor cyclopamine (Cy) and the BMP antagonist noggin. rh-SHH increased the expression of BMP-2 and -4 mRNA, as well as levels of phosphorylated Akt, ERK, p38, and JNK, and of MAPK and NF-κB activation, which were reversed by noggin, Cy, and BMP-2 siRNA. Collectively, this study is the first to demonstrate that SHH can promote cell growth and cell osteoblastic/cementoblastic differentiation via BMP pathway. Thus, SHH plays important roles in the development of periodontal tissue, and might represent a new therapeutic target for periodontitis and periodontal regeneration.
KeywordsSonic hedgehog Cementoblasts Differentiation Signal pathways
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 2012R1A5A2051384).
Compliance with Ethical Standards
Conflict of Interest
Won-Jung Bae, Q-Schick Auh, Hyun-Chang Lim, Gyu-Tae Kim, Hyun-Soo Kim and Eun-Cheol Kim declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
The animal experimental procedures were performed in accordance with the ethical guidelines and were approved by the Kyung Hee University Animal Care Committee (Seoul, Korea).
- 4.Foster BL, Somerman MJ (2012) Cementum. In: McCauley LK, Somerman MJ (eds) Mineralized tissues in oral and craniofacial science: biological principles and clinical correlates, 1st edn. Wiley-Blackwell, Ames, pp 169–192Google Scholar
- 21.Seidel K, Ahn CP, Lyons D, Nee A, Ting K, Brwonell I, Cao T, Carano RA, Curran T, Schober M, Fuchs E, Joyner A, Marin GR, de Sauvage FJ, Klein OD (2010) Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor. Development 137(22):3753–3761PubMedPubMedCentralCrossRefGoogle Scholar
- 24.Spinella-Jaegle S, Rawadi G, Kawai S, Gallea S, Faucheu C, Mollat P, Courtois B, Bergaud B, Ramez V, Blanchet AM, Adelmant G, Baron R, Roman-Roman S (2001) Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci 114(Pt 11):2085–2094PubMedGoogle Scholar
- 34.Spinella-Jaeqle S, Rawadi G, Kawai S, Gallea S, Faucheu C, Mollat P (2001) Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci 114(Pt 111):2085–2094Google Scholar
- 54.Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, Eaton E, Iwakura A, Tsutsumi Y, Hamada H, Kishimoto S, Thorne T, Kishore R, Losordo DW (2006) Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation 113(20):2413–2424PubMedCrossRefGoogle Scholar
- 61.Xiao G, Gopalakrishnan R, Jiang D, Reith E, Benson M, Franceschi RT (2002) Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J Bone Miner Res 17(1):101–110PubMedCrossRefGoogle Scholar