title: Sonic hedgehog signaling drives proliferation of synoviocytes in rheumatoid arthritis: a possible novel therapeutic target.
abstract: Sonic hedgehog (Shh) signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA) is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS). We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1) in RA synovial tissues was examined by immunohistochemistry (IHC) and in FLS by IHC, immunofluorescence (IF), quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P < 0.05). Cyclopamine (a specific inhibitor of Shh signaling) decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China ; Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China ; Department of Rheumatology of Zhongshan Affiliated Hospital, Sun Yat-Sen University, Zhongshan, Guangdong 528400, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Shangling
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Weixiang
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Minqi
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Feng
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Huang
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D018501:Antirheumatic Agents; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine
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