title: Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis.
abstract: OBJECTIVE
  To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS.
  
  
  METHODS
  BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs.
  
  
  RESULTS
  AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored.
  
  
  CONCLUSIONS
  The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin.
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Deng
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Su
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Deng
authors.initials: D
authors.lastname: Li
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Shen
mesh_terms: D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D002352:Carrier Proteins; D016207:Cytokines; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D000099176:Noggin Protein; C525718:BMP2 protein, human; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human