Beta2-microglobulin (beta2M) amyloidosis is a destructive osteoarticular disease that affects dialysis patients. On pathologic analysis, the synovium and bone have amyloid deposits which contain beta2M and serum amyloid P component (SAP), a protein common to all amyloidoses. The pathophysiology of this disease and the reason for the skeletal predilection is unknown. Preliminary studies demonstrated that beta2M induces bone resorption through osteoclast activation. However, clinically, the amyloid deposition occurs mainly near joints, suggesting that synovial involvement may be necessary for the formation of amyloid. The P.I. has developed an in vitro model of the joint by co-culturing rabbit synovial fibroblasts with neonatal mouse calvariae placed on a steel support on top of the synoviocytes. The purpose of this study is to evaluate the effects of beta2M in this in vitro joint model and determine the pathophysiology of beta2M bone destruction by testing the following hypotheses: To test the hypothesis that beta2M amyloidosis is due to the interaction of beta2M with synoviocytes, the effects of beta2M on bone turnover will be evaluated by determining net calcium flux, bone cell enzyme release and quantitating bone changes histomorphometrically. To test the hypothesis that amyloid fibril formation in bone requires synovium in the presence of beta2M and SAP, the bone in synoviocyte/bone co-cultures will be examined for amyloid deposition and adjacent bone cell alterations in the presence of various concentrations of beta2M and SAP. To test the hypothesis that the mechanism of action of beta2M induced bone destruction in beta2M amyloidosis is excessive proteolysis due to the stimulation of synoviocyte collagenase and/or inhibition of tissue inhibitor of metalloproteinase (TIMP) activity, collagenase and TIMP transcription and concentrations will be determined. Beta2M isolated from patients with acute renal failure and chronic renal failure with and without beta2M amyloidosis will be utilized.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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