title: Interleukin-1β promotes proliferation and inhibits differentiation of chondrocytes through a mechanism involving down-regulation of FGFR-3 and p21.
abstract: The proinflammatory cytokine IL-1β is elevated in many childhood chronic inflammatory diseases as well as obesity and can be associated with growth retardation. Here we show that IL-1β affects bone growth by directly disturbing the normal sequence of events in the growth plate, resulting in increased proliferation and widening of the proliferative zone, whereas the hypertrophic zone becomes disorganized, with impaired matrix structure and increased apoptosis and osteoclast activity. This was also evident in vitro: IL-1β increased proliferation and caused a G1-to-S phase shift in the cell cycle in ATDC5 chondrocytes, accompanied by a reduction in fibroblast growth factor receptor-3 (FGFR-3) and its downstream gene, the cell-cycle inhibitor p21 and its family member p57, whereas the cell-cycle promoter E2F-2 was increased. The reduction in FGFR-3, p21, and p57 was followed by delayed cell differentiation, manifested by decreases in proteoglycan synthesis, mineralization, alkaline phosphatase activity, and the expression of Sox9, RunX2, collagen type II, collagen type X, and other matrix proteins. Taken together, we suggest that IL-1β alters normal chondrogenesis and bone growth through a mechanism involving down-regulation of FGFR-3 and p21.
authors.affiliation: Institute of Biochemistry and Nutrition, The Robert H. Smith Faculty of Agriculture, Food, and Environment, The Hebrew University, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Stav
authors.initials: S
authors.lastname: Simsa-Maziel
authors.forename: Efrat
authors.initials: E
authors.lastname: Monsonego-Ornan
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006132:Growth Plate / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D053583:Interleukin-1beta; D051498:Receptor, Fibroblast Growth Factor, Type 3