IGF/IGFBP axis in cartilage and bone in osteoarthritis pathogenesis.
In the context of joint biology, insulin-like growth factor-1 (IGF-1) is the most likely candidate to affect the anabolism of cartilage matrix molecules. Mechanisms for controlling the effects of IGF-1 include alterations in the level of this growth factor, its receptor and/or the IGF-1 affinity or availability to its receptor. Disturbance of any one of the above elements may induce a disregulation of the mechanisms involved in the local control of joint tissue integrity. This review focuses on recent studies of the IGF system, and the potential relevance of these results to in vivo effects in osteoarthritic (OA) tissues. It has been shown that, although the IGF-1's expression and synthesis are increased in OA cartilage, chondrocytes are hyporesponsive to IGF-1 stimulation. This phenomenon appears to be related, at least in part, to an increased level of IGF-binding proteins (IGFBP). The IGFBP have a high affinity for IGF-1, and appear to be important biomodulators for IGF action. Though to date seven IGFBP have been cloned and sequenced, disregulation in IGFBP-3 and -4 appears instrumental to arthritic disorders. Proteolytic activity directed against IGFBP has been found in both cartilage and bone; this activity appears to belong to serine- and/or metallo-proteases families. It has been suggested that a thickening of the subchondral bone participates in OA pathophysiology, and that IGF-1 production by bone and/or subchondral bone cells may contribute to these changes. An abnormal regulation of subchondral bone formation via an increase in the local activation of IGF-1 in bone cells, possibly via abnormal IGFBP synthesis due to aberrant PA/plasmin regulation of the IGF-I/IGFBP system, is believed to be a plausible hypothesis.
Martel-Pelletier
J
J
Osteoarthritis Research Unit, Centre de Recherche L.-C. Simard, CHUM, Montréal, Québec, Canada.
Di Battista
J A
JA
Lajeunesse
D
D
Pelletier
J P
JP
D001842:Bone and Bones / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D006706:Homeostasis; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D010003:Osteoarthritis / Q000209:etiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D016207:Cytokines; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I