title: Role of Fibulin 3 in Aging-Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage.
abstract: The EFEMP1 gene encoding fibulin 3 is specifically expressed in the superficial zone (SZ) of articular cartilage. The aims of this study were to examine the expression patterns of fibulin 3 in the knee joints during aging and during osteoarthritis (OA) and to determine the role of fibulin 3 in the pathogenesis of OA.
  
  
  
  Immunohistochemical analysis was performed on normal and OA knee cartilage samples from humans and mice. Experimental OA was induced in wild-type and fibulin 3-/-mice, and the severity of OA was evaluated by histologic scoring. To examine fibulin 3 function, human chondrocyte monolayer cultures were transfected with small interfering RNA (siRNA), followed by quantitative polymerase chain reaction and Western blot analyses. Human bone marrow-derived mesenchymal stem cells (BM-MSCs) were transduced with an EFEMP1 lentivirus and analyzed for markers of chondrogenesis.
  
  
  
  Fibulin 3 was specifically expressed in the SZ of normal knee joint cartilage from humans and mice, and the expression levels declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin 3-/-mice compared with wild-type mice. Fibulin 3 expression was high in undifferentiated human BM-MSCs and decreased during chondrogenesis. Suppression of fibulin 3 by siRNA significantly increased the expression of SOX9, type II collagen, and aggrecan in human articular chondrocytes, while overexpression of fibulin 3 inhibited chondrogenesis in BM-MSCs.
  
  
  
  Fibulin 3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin 3 regulates differentiation of adult progenitor cells, and its aging-related decline is an early event in the pathogenesis of OA. Preventing aging-associated loss of fibulin 3 or restoring it to normal levels in SZ chondrocytes has the potential to delay or prevent the onset of OA.
authors: The Scripps Research Institute, La Jolla, California, and Osaka Medical College, Osaka, Japan.
authors: Akihiko
authors: A
authors: Hasegawa
authors: The Scripps Research Institute, La Jolla, California.
authors: Tomo
authors: T
authors: Yonezawa
authors: The Scripps Research Institute, La Jolla, California.
authors: Noboru
authors: N
authors: Taniguchi
authors: The Scripps Research Institute, La Jolla, California.
authors: Koji
authors: K
authors: Otabe
authors: The Scripps Research Institute, La Jolla, California.
authors: Yukio
authors: Y
authors: Akasaki
authors: The Scripps Research Institute, La Jolla, California.
authors: Tetsuya
authors: T
authors: Matsukawa
authors: The Scripps Research Institute, La Jolla, California.
authors: Masahiko
authors: M
authors: Saito
authors: Osaka Medical College, Osaka, Japan.
authors: Masashi
authors: M
authors: Neo
authors: University of Arizona, Tucson.
authors: Lihua Y
authors: LY
authors: Marmorstein
authors: The Scripps Research Institute, La Jolla, California.
authors: Martin K
authors: MK
authors: Lotz
mesh_terms: D000328:Adult; D000375:Aging; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C119630:EFEMP1 protein, human; C492278:Efemp1 protein, mouse; D016326:Extracellular Matrix Proteins