title: Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways.
abstract: The balance between anabolic and catabolic signaling pathways is critical in maintaining cartilage homeostasis and its disturbance contributes to joint diseases such as osteoarthritis (OA). A unique mechanism that modulates the activity of cell signaling pathways is controlled by extracellular heparan endosulfatases Sulf-1 and Sulf-2 (Sulfs) that are overexpressed in OA cartilage. This study addressed the role of Sulfs in cartilage homeostasis and in regulating bone morphogenetic protein (BMP)/Smad and fibroblast growth factor (FGF)/Erk signaling in articular cartilage. Spontaneous cartilage degeneration and surgically induced OA were significantly more severe in Sulf-1(-/-) and Sulf-2(-/-) mice compared with wild-type mice. MMP-13, ADAMTS-5, and the BMP antagonist noggin were elevated whereas col2a1 and aggrecan were reduced in cartilage and chondrocytes from Sulf(-/-) mice. Articular cartilage and cultured chondrocytes from Sulf(-/-) mice showed reduced Smad1 protein expression and Smad1/5 phosphorylation, whereas Erk1/2 phosphorylation was increased. In human chondrocytes, Sulfs siRNA reduced Smad phosphorylation but enhanced FGF-2-induced Erk1/2 signaling. These findings suggest that Sulfs simultaneously enhance BMP but inhibit FGF signaling in chondrocytes and maintain cartilage homeostasis. Approaches to correct abnormal Sulf expression have the potential to protect against cartilage degradation and promote cartilage repair in OA.
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Otsuki
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Hanson
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyaki
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Grogan
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Martin K
authors.initials: MK
authors.lastname: Lotz
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071116:ADAMTS5 Protein; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013429:Sulfatases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D053509:Matrix Metalloproteinase 13; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; D013429:Sulfatases; D015238:Sulfotransferases; D000099176:Noggin Protein; C525820:bmp7 protein, mouse; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse; C498489:Adamts5 protein, mouse; C507081:Mmp13 protein, mouse