title: Extracellular and intracellular mechanisms of mechanotransduction in three-dimensionally embedded rat chondrocytes.
abstract: OBJECTIVE
  Articular cartilage homeostasis involves modulation of chondrocyte matrix synthesis in response to mechanical stress (MS). We studied extracellular and intracellular mechanotransduction pathways mediating this response.
  
  
  METHODS
  We first confirmed rapid up-regulation of the putative chondro-protective cytokine, interleukin (IL)-4, as an immediate response to MS. We then studied the role of IL-4 by investigating responses to exogenous IL-4 or a specific IL-4 inhibitor, combined with MS. Next we investigated the intracellular second messengers. Since chondrocyte phenotype alters according to the extracellular environment, we characterized the response to mechanotransduction in 3-dimensionally embedded chondrocytes.
  
  
  RESULTS
  Expression of aggrecan and type II collagen was significantly up-regulated by exogenous IL-4 whereas MS-induced matrix synthesis was inhibited by an IL-4 blocker. Further, MS-induced matrix synthesis was completely blocked by a p38 MAPK inhibitor, while it was only partially blocked by inhibitors of other putative second messengers.
  
  
  CONCLUSIONS
  IL-4 mediates an extracellular pathway of mechanotransduction, perhaps via an autocrine/paracrine loop, while p38 mediates an intracellular pathway prevalent only in a 3-dimensional environment.
authors.affiliation: Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Shioji
authors.affiliation: Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Imai
authors.affiliation: Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Matsusue
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015847:Interleukin-4