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 matr ix molecules. Mechanisms for controlling the effects of IGF-1 include alterations in the level of this growth factor, its receptor and/or th e IGF-1 affinity or availability to its receptor. Disturbance of any o ne of the above elements may induce a disregulation of the mechanisms involved in the local control of joint tissue integrity. This review f ocuses on recent studies of the IGF system, and the potential relevanc e 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 hav e a high affinity for IGF-1, and appear to be important biomodulators for IGF action. Though to date seven IGFBP have been cloned and sequen ced, 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 thic kening of the subchondral bone participates in OA pathophysiology, and that IGF-1 production by bone and/or subchondral bone cells may contr ibute to these changes. An abnormal regulation of subchondral bone for mation via an increase in the local activation of IGF-1 in bone cells, possibly via abnormal IGFBP synthesis due to aberrant PAI plasmin reg ulation of the IGF-1/IGFBP system, is believed to be a plausible hypot hesis.