Upregulation of BMP2/4 signaling increases both osteoblast-specific marker expression and bone marrow adipogenesis in Gja1Jrt/+ stromal cell cultures


Tanya Zappitelli, Frieda Chen, and Jane E. Aubin


Gja1Jrt/+ mice carry a mutation in one allele of the gap junction protein, alpha 1 gene (Gja1), resulting in a G60S Connexin 43 (Cx43) mutant protein that is dominant negative for Cx43 protein production of <50% of wild type (WT) levels and significantly reduced gap junction formation and function in osteoblasts and other Cx43-expressing cells. Earlier we reported that Gja1Jrt/+ mice exhibited early-onset osteopenia caused by activation of osteoclasts secondary to activation of osteoblast lineage cells, which expressed increased RANKL and produced an abnormal resorption-stimulating bone matrix, high in BSP content. Gja1Jrt/+ mice also displayed early and progressive bone marrow atrophy, with a significant increase in bone marrow adiposity versus WT littermates but no increase in adipose tissues elsewhere in the body. BMP2/4 production and signaling were increased in Gja1Jrt/+ trabecular bone and osteogenic stromal cell cultures, which contributed to the upregulated expression of osteoblast-specific markers (e.g. Bsp and Ocn) in Gja1Jrt/+ osteoblasts and increased Pparg2 expression in bone marrow-derived adipoprogenitors in vitro. The elevated levels of BMP2/4 signaling in G60S Cx43-containing cells resulted at least in part from elevated levels of cAMP. We conclude that up-regulation of BMP2/4 signaling in trabecular bone and/or stromal cells increases osteoblast-specific marker expression in hyperactive Gja1Jrt/+ osteoblasts, and may also increase bone marrow adipogenesis by up-regulation of Pparg2 in the Cx43-deficient Gja1Jrt/+ mouse model.

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