Expression profile of osteoclasts treated with bisphosphonates
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63009 | GEO | 2014/11/06
SECONDARY ACCESSION(S): PRJNA266418
REPOSITORIES: GEO
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Project description:Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. They inhibit the activities of the osteoclasts, the bone resorption cells. While bisphosphonates are known to block farnesyl pyrophsophate synthase to exert their anti-resorptive action, the detailed mechanism is not well understood. Examining the change in expression profile before and after bisphosphonate treatment in the osteoclasts might shed some light on the biological pathways that are perturbed. Osteoclastic precursor cells were treated with (or without) bisphosphonates (alendronate or risedronate) during their differentiation into mature osteoclasts.
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Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1, including cathepsin G and myeloperoxidase. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed membrane proteins and v-ATPases required for bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
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