Effect of Stem Cell Factor, Interleukin–6, Nitric Oxide and Transforming Growth Factor–β on the Osteoclast Differentiation Induced by 1α,25–(OH)2D3in Primary Murine Bone Marrow Cultures

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Abstract
Osteotropic hormones and cytokines are involved in the differentiation of osteoclast progenitors from haematopoietic stem cells to multinucleated osteoclasts which mediate bone resorption. Stem cell factor, interleukin–6, nitric oxide, and transforming growth factor–β are implicated in the regulation of bone resorption by osteoclast. We test whether stem cell factor, interleukin–6, nitric oxide, and transforming growth factor–β affect the generation of osteoclast–like multinucleated cells induced by 1α,25–(OH)2D3. 1α,25–(OH)2D3increases the generation of osteoclast–like cells retaining osteoclast characteristics including multinuclearity and positive staining for tartrate–resistant acid phosphatase. Combined treatment of stem cell factor with interleukin–6 synergistically potentiates the ability of 1α,25–(OH)2D3to generate tartrate–resistant acid phosphatase–positive multinucleated cells. However, either stem cell factor or interleukin–6 alone does not induce the generation of tartrate–resistant acid phosphatase–positive multinucleated cells. Transforming growth factor–β produces a biphasic effect on osteoclast generation induced by 1α,25–(OH)2D3. Transforming growth factor–β stimulates osteoclast generation at low concentration (0.1 ng/ml) whereas it suppresses the formation of osteoclast–like cell at higher concentration (1 ng/ml). Sodium nitroprusside, a donor of nitric oxide, almost completely inhibits the generation of 1α,25–(OH)2D3–induced osteoclast at high concentration (100 μM), but it significantly enhances the osteoclast generation at low concentrations (3 μM). These results suggest that stem cell factor, interleukin–6, transforming growth factor–β, and nitric oxide interact with 1α,25–(OH)2D3to modulate the differentiation of hematopoietic precursors toward committed osteoclast precursors.