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Status |
Public on Jun 05, 2021 |
Title |
ELMO1 is a promoter of osteoclast function and bone loss |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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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Overall design |
The experiment consisted of two conditions - mature osteoclasts differentiated from the bone marrow of either Elmo1+/– or Elmo1–/– mice. Each condition consisted of four biological replicates.
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Contributor(s) |
Arandjelovic S, Perry JA, Zhou M, Ceroi A, Smirnov I, Walk SF, Shankman LS, Cambre I, Onengut-Gumuscu S, Elevaut D, Conrads TP, Ravichandran KS |
Citation(s) |
34404802 |
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Submission date |
Jan 14, 2021 |
Last update date |
Sep 04, 2021 |
Contact name |
Justin Shaun Arnold Perry |
E-mail(s) |
perryj@mskcc.org
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Phone |
6468883928
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Organization name |
Sloan Kettering Institute for Cancer Research
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Department |
Immunology Program
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Lab |
Perry Lab
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Street address |
408 East 69th Street, 408-15
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City |
New York |
State/province |
New York |
ZIP/Postal code |
10065 |
Country |
USA |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (8)
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Relations |
BioProject |
PRJNA692169 |
SRA |
SRP301756 |
Supplementary file |
Size |
Download |
File type/resource |
GSE164826_DESeq2.csv.gz |
2.0 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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