Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint

Author:

Whellams EJ,Maile LA,Fernihough JK,Billingham ME,Holly JM

Abstract

Increased concentrations of insulin-like growth factor (IGF) system components have previously been observed in rheumatoid arthritis (RA) and osteoarthritis (OA); however, disruption of the IGF axis and the implications for the disease process remain largely unaddressed. This study was undertaken to characterise the IGF binding protein (IGFBP)-3 proteolysis and complex formation systems in synovial fluid and to investigate changes in these systems in arthritic disease, and their impact on the availability of IGF. Western blotting or autoradiography of SDS gels was used to visualise IGFBP-3 or its proteolysis. IGF-I and IGFBP-3 concentrations were determined by radioimmunoassays and acid-labile subunit (ALS) was measured by ELISA. A shift in distribution of IGFBP-3 and IGF-I in RA and OA synovial fluids (RASynF, OASynF) and an associated increase in ALS suggested the presence of 150 kDa ternary complexes. IGFBP-3 proteolysis was decreased in RASynF and OASynF, but was apparent in size-fractionated fluid and resembled serum activity. The presence of serum-like inhibitors of IGFBP-3 proteolysis in RASynF was also demonstrated by the ability of this fluid, and 150 kDa fractions from its size fractionation, to inhibit IGFBP-3 proteolysis in the other synovial fluid. A marked disruption in the IGF system was observed, as considerably more IGF-I was retained in ternary complexes. We also classified the IGFBP-3 proteolysis system in synovial fluid and found it to be disturbed in RASynF and OASynF. These changes may be caused by an increased flux of circulatory proteins into synovial fluid, resulting from an inflammation-induced increase in vascular permeability. The net result in RA and OA would be a decrease in IGF availability in arthritic joints, and therefore loss of a potential anabolic stimulus. This disruption to the IGF axis would influence disease progression in RA and OA.

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

Cited by 28 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Cartilage and Chondrocytes;Kelley's Textbook of Rheumatology;2013

2. Growth factor regulation of intracellular pH homeostasis under hypoxic conditions in isolated equine articular chondrocytes;Journal of Orthopaedic Research;2012-09-14

3. Insulin-Like Growth Factor Physiology;Endocrinology and Metabolism Clinics of North America;2012-06

4. Regulatory Functions of Insulin-like Growth Factor Binding Proteins in Osteoarthritis;International Journal of Immunopathology and Pharmacology;2011-01

5. On the role of diffusible binding partners in modulating the transport and concentration of proteins in tissues;Journal of Theoretical Biology;2010-03

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