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- Open Access
Effects of hyper-resorptive osteoclasts on SHIP-deficient mice
- Jason M Weaver1
© Biomed Central Ltd 2002
- Received: 26 September 2002
- Accepted: 19 November 2002
- Published: 19 November 2002
- Paget Disease
Mature osteoclasts are specialized macrophage polykaryons formed by the fusion of mononuclear progenitors of the monocyte/macrophage lineage. They function as the primary resorptive cell of bone and modulate the formation of the skeleton and regulation of its mass. The rate of bone degradation is dependent upon the osteoclast number and the bone-resorptive capacity upon the mature osteoclast. Osteoclast precursor survival and differentiation is dependent on the signaling of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL). The intracellular signaling that activates these potent cytokines has not been fully elucidated, but includes phosphatidylinositol 3-kinase (PI3-K) activity. Phosphatidylinositol-3,4,5-triphosphate (PIP3), a major product of PI3-K activity, is specifically recognized and cleaved at a 5’-phosphate group by the Src homology (SH) 2-containing inositol-5-phosphatase (SHIP) protein. The dephosphorylation of PIP-3 by SHIP implicates the proteins' ability to affect the function and signaling of osteoclasts. Here the group assesses and fully characterizes the bone phenotype and osteoclastogenic regulations of a SHIP -/- mouse.
The mineral apposition and bone formation rates were acquired on calvariae and shown to be not significantly different indicating that the SHIP -/- has accelerated bone resorption reflecting the osteoporotic phenotype. SHIP is a negative regulator of osteoclastogenesis and the absence of SHIP increases the sensitivity of M-CSF-dependent bone-marrow macrophages to essential osteoclastogenic cytokines M-CSF and RANKL, resulting in increased osteoclast number, size, nuclei and decreased apoptosis. The increases are synonymous with pathology found in Paget's Disease patients who display enlarged and deformed bones. Preosteoclasts cultured on bone wafers resorbed more bone and formed deeper pits, with an approximately 60-fold increase in IL-6 levels, implicating IL-6 in regulating resorptive activity of osteoclasts and as a potential mediator of osteoclast function in Paget's Disease. Functional relevance of the increased osteoclast number in long bone was assessed by femoral architectural and metaphyseal morphology and biomechanical parameters. The areal bone–mineral density was diminished and the femoral diaphyseal bone stiffness/strength decreased due to reduced cross-sectional size rather than to a defect in material.
Gene targeting, microcomputed tomography scanning, dual energy x-ray absorptiometry, histomorphometry, resorption pit assay
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