title: Chondrogenic progenitor cells promote vascular endothelial growth factor expression through stromal-derived factor-1.
abstract: Vascular endothelial growth factor (VEGF) is elevated in joint fluids from patients diagnosed with osteoarthritis (OA). VEGF is known to contribute to vascular tidemark invasion and osteophyte formation, which are classic features of advanced OA. Among the factors that may drive VEGF accumulation in diseased joints, stromal cell-derived factor-1α (SDF-1α) is a likely culprit, as it is enriched in synovial fluids from osteoarthritic joints and is a potent inducer of VEGF expression. Chondrogenic progenitor cells (CPCs) that overexpress SDF-1α are abundant in osteoarthritic cartilage, implicating them in elevating synovial SDF-1α levels. Here we conducted a series of experiments to determine the potential for CPCs to stimulate VEGF expression via autocrine and paracrine mechanisms.
  
  
  
  Immunohistochemistry, immunoblotting, and PCR were used to evaluate the effects of SDF-1α on VEGF expression in CPCs and chondrocytes, and the effects of CPC-conditioned medium on chondrocytes. An SDF-1α receptor antagonist and inhibitors of mitogen-activated protein kinases (MAPKs) were used to probe the pathway linking SDF-1 with VEGF expression in CPCs.
  
  
  
  SDF-1α and CPC-conditioned medium stimulated VEGF expression in chondrocytes. In both chondrocytes and CPCs, SDF-1α stimulated increased VEGF expression via C-X-C chemokine receptor type 4 (CXCR4), a cell-surface SDF-1α receptor. This response in CPCs is dependent on p38 MAPK activation, but not on ERK or c-Jun N-terminal kinase (JNK) activation.
  
  
  
  By secreting SDF-1α, CPCs stimulate VEGF expression in nearby cells. The co-expression of SDF-1 and its receptor by CPCs indicates they are capable of self-sustained VEGF expression via an autocrine mechanism.
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: 13804539667@163.com.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA; Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA. Electronic address: cheng-zhou@uiowa.edu.
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA. Electronic address: zhengh@wudosis.wustl.edu.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: zhangzhiyi2014@163.com.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: myfyxd@163.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA; Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA. Electronic address: james-martin@uiowa.edu.
authors.forename: J A
authors.initials: JA
authors.lastname: Martin
mesh_terms: D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology*; D016133:Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013234:Stem Cells / Q000378:metabolism*; D046509:Tissue Culture Techniques; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; D042442:Vascular Endothelial Growth Factors; D020928:Mitogen-Activated Protein Kinases
keywords: CXCR4; Chondrogenic progenitor cells (CPCs); SDF-1α; Vascular endothelial growth factor (VEGF); p38 MAPK