title: Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist.
abstract: Increased chondrocyte hypertrophy is often associated with cartilage joint degeneration in human osteoarthritis patients. Matrilin-3 knock-out (Matn3 KO) mice exhibit these features. However, the underlying mechanism is unknown. In this study, we sought a molecular explanation for increased chondrocyte hypertrophy in the mice prone to cartilage degeneration. We analyzed the effects of Matn3 on chondrocyte hypertrophy and bone morphogenetic protein (Bmp) signaling by quantifying the hypertrophic marker collagen type X (Col X) gene expression and Smad1 activity in Matn3 KO mice in vivo and in Matn3-overexpressing chondrocytes in vitro. The effect of Matn3 and its specific domains on BMP activity were quantified by Col X promoter activity containing the Bmp-responsive element. Binding of MATN3 with BMP-2 was determined by immunoprecipitation, solid phase binding, and surface plasmon resonance assays. In Matn3 KO mice, Smad1 activity was increased more in growth plate chondrocytes than in wild-type mice. Conversely, Matn3 overexpression in hypertrophic chondrocytes led to inhibition of Bmp-2-stimulated, BMP-responsive element-dependent Col X expression and Smad1 activity. MATN3 bound BMP-2 in a dose-dependent manner. Multiple epidermal growth factor (EGF)-like domains clustered together by the coiled coil of Matn3 is required for Smad1 inhibition. Hence, as a novel BMP-2-binding protein and antagonist in the cartilage extracellular matrix, MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity.
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Trehan
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guan
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Changqi
authors.initials: C
authors.lastname: Sun
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Moore
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Chathuraka T
authors.initials: CT
authors.lastname: Jayasuriya
authors.affiliation: From the Cell and Molecular Biology Laboratory, Department of Orthopaedics, Warren Alpert Medical School, Brown University/Rhode Island Hospital, Providence, Rhode Island 02903 Qian_chen@Brown.edu.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D024121:Collagen Type X / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D064235:Matrilin Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D055396:Bone Morphogenetic Protein 2; D024121:Collagen Type X; D064235:Matrilin Proteins; D010750:Phosphoproteins; D051898:Smad1 Protein; D051902:Smad5 Protein
keywords: Bone Morphogenetic Protein (BMP); Cartilage; Cartilage Biology; Chondrocyte; Extracellular Matrix; Extracellular Matrix protein