The αvβ3 integrin as a therapeutic target for inhibition of bone resorption
© The Author(s) 2004
Published: 13 September 2004
An early feature of inflammatory arthritis is an increase in the number, size and activity of osteoclasts leading to the destruction of periarticular and subchondral bone and mineralized cartilage . Osteoclastic resorption is regulated by a number of processes, including the proliferation, differentiation and recruitment of osteoclast precursors, the migration and activation of mature osteoclasts, and programmed cell death. Regulatory mechanisms involve soluble mediators, cell–cell and cell–matrix interactions. The latter involve integrins – heterodimeric receptors that link the cytoskeleton to the extracellular matrix and mediate outside-in and inside-out signaling. Mature osteoclasts express three integrins (αvβ3, αvβ1 and α2β1), with the α vβ3 vitronectin receptor predominating.
We used a single cell assay to demonstrate that macrophage-colony stimulating factor (M-CSF) and transforming growth factor beta are chemotaxins for mammalian osteoclasts. Interestingly, the RGD-containing disintegrin echistatin, which binds αvβ3 integrin, inhibited M-CSF-induced chemotaxis at concentrations as low as 0.1 nM ; whereas it did not inhibit migration induced by transforming growth factor beta .
We have recently examined the effects of Vitaxin®, a humanized monoclonal antibody that blocks human and rabbit αvβ3 integrins . Vitaxin® caused a concentration-dependent decrease in the number of rabbit osteoclasts attached to plastic. Moreover, Vitaxin® inhibited resorption by rabbit osteoclasts cultured on slices of bovine bone (Vitaxin® at 0.7 nM reduced resorption by ~50%). Vitaxin® also suppressed bone resorption by in vitro-derived human osteoclasts, with a maximum of 63% inhibition observed at concentrations greater than 2 nM. Vitaxin® does not react with rodent αvβ3 integrin; therefore, we used a blocking anti-rat αvβ3 integrin to assess effects on rat osteoclast motility. This antibody induced rapid retraction of M-CSF-treated rat osteoclasts but, unlike echistatin, did not inhibit chemotaxis induced by M-CSF.
Evidence from our laboratories and others, using disintegrins, antibodies, RGD-containing peptides and small molecules that bind the αvβ3 integrin, point to its potential as a target for the development of antiresorptive therapies. The role of αvβ3 integrins in angiogenesis may make such therapeutics especially useful for the treatment of rheumatoid arthritis and metastatic bone disease. Differences in responses to various agents and to genetic ablation of αvβ3 integrins point to multiple underlying mechanisms and underscore the need for further investigations.
These studies were supported in part by the Canadian Institutes of Health Research and by the Canadian Arthritis Network.
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