ELEVATED LEVELS OF INSULIN-LIKE-GROWTH-FACTOR (IGF) BINDING PROTEIN-3IN RHEUMATOID-ARTHRITIS SYNOVIAL-FLUID INHIBIT STIMULATION BY IGF-I OF ARTICULAR CHONDROCYTE PROTEOGLYCAN SYNTHESIS

The objective of this study was to quantify insulin-like growth factor (IGF) binding proteins (IGFBPs) in the synovial fluid (SF) and plasma of patients with rheumatic diseases and to study the role of these pr oteins in the regulation of cartilage proteoglycan (PG) synthesis. Imm unological determination of IGFBP-2, IGFBP-3, TGF-I, IGF-II, interleuk in-1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha) was undertaken in the SF and plasma of 115 patients with rheumatoid arthr itis (RA; n = 53), osteoarthritis (OA; n = 44) and other rheumatic dis orders. We also determined the effects of SF on bovine cartilage pc sy nthesis in culture. IGFBP-2 and IGFBP-3 were elevated in the plasma (b y 38% and 28%, respectively) and SF (by 56% and 59%, respectively) of patients with RA compared to age- and sex-matched OA controls (determi ned by RIA and confirmed by Western ligand blot). IGF-I and IGF-II did not differ significantly between the two groups. OA SE and, to a less er extent, RA SF stimulated cartilage PG synthesis in culture, and mor e than 60% of this activity was neutralised by a specific monoclonal a nti-IGF-I antibody. Human IGFBP-3 dose-dependently inhibited the stimu lation of cartilage PG synthesis effected by SF or human IGF-I. In RA patients, the SF concentration of IGFBP-3 was positively correlated wi th SF levels of IL-1 beta and TNF alpha, with the serum level of C-rea ctive protein and with the erythrocyte sedimentation rate. We conclude d that IGF-I is, under the conditions studied, the most important anab olic factor in human SF with respect to articular cartilage PG synthes is. The bioactivity of IGF-I in joints is modulated by IGFBP-3, which is elevated in RA SF compared to OA SE Elevated IGFBP-3 in RA SF may r educe the availability of IGF-I to articular chondrocytes, thus interf ering with cartilage PG synthesis in RA.