title: Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13.
abstract: We investigated the role of periostin, an extracellular matrix protein, in the pathophysiology of osteoarthritis (OA). In OA, dysregulated gene expression and phenotypic changes in articular chondrocytes culminate in progressive loss of cartilage from the joint surface. The molecular mechanisms underlying this process are poorly understood. We examined periostin expression by immunohistochemical analysis of lesional and nonlesional cartilage from human and rodent OA knee cartilage. In addition, we used small interfering (si)RNA and adenovirus transduction of chondrocytes to knock down and up-regulate periostin levels, respectively, and analyzed its effect on matrix metalloproteinase (MMP)-13, a disintegrin and MMP with thrombospondin motifs (ADAMTS)-4, and type II collagen expression. We found high periostin levels in human and rodent OA cartilage. Periostin increased MMP-13 expression dose [1-10 µg/ml (EC50 0.5-1 μg/ml)] and time (24-72 h) dependently, significantly enhanced expression of ADAMTS4 mRNA, and promoted cartilage degeneration through collagen and proteoglycan degradation. Periostin induction of MMP-13 expression was inhibited by CCT031374 hydrobromide, an inhibitor of the canonical Wnt/β-catenin signaling pathway. In addition, siRNA-mediated knockdown of endogenous periostin blocked constitutive MMP-13 expression. These findings implicate periostin as a catabolic protein that promotes cartilage degeneration in OA by up-regulating MMP-13 through canonical Wnt signaling.
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada mukundan.attur@nyumc.org.
authors.forename: Mukundan
authors.initials: M
authors.lastname: Attur
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shimada
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tachida
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Statman
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Glyn
authors.initials: G
authors.lastname: Palmer
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kirsch
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.affiliation: *Division of Rheumatology, Department of Medicine, Department of Cell Biology, and Department of Orthopaedic Surgery, New York University (NYU) School of Medicine and NYU Langone Medical Center, New York, New York, USA; Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, Florida, USA; and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse
keywords: ADAMTS; Wnt signaling; chondrocytes; posttraumatic osteoarthritis