ELMO1 signaling is a promoter of osteoclast function and bone loss
| Autor: | Laura S. Shankman, Ming-Ming Zhou, Kodi S. Ravichandran, Scott F. Walk, Sanja Arandjelovic, Dirk Elewaut, Adam Ceroi, Thomas P. Conrads, Igor Smirnov, Isabelle Cambré, Suna Onengut-Gumuscu, Justin S. A. Perry |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Osteoporosis
PROTEIN General Physics and Astronomy Arthritis Osteoclasts Cathepsin G MOUSE DEGRADATION-PRODUCTS DISEASE chemistry.chemical_compound Mice Medicine and Health Sciences Mice Knockout Multidisciplinary RNA sequencing Cell biology Bone quality and biomechanics medicine.anatomical_structure ELMO1 Mechanisms of disease Female Cell signalling Signal Transduction musculoskeletal diseases Proteases DATABASE Science Ovariectomy Biology General Biochemistry Genetics and Molecular Biology Bone resorption Article Osteoprotegerin Osteoclast medicine Animals NUCLEOTIDE EXCHANGE ONE-STEP ELISA Bone Resorption Bone Adaptor Proteins Signal Transducing Biology and Life Sciences General Chemistry X-Ray Microtomography medicine.disease Bone Diseases Metabolic chemistry DOCK180 CELLS CRISPR-Cas Systems INHIBITORS Transcriptome |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) NATURE COMMUNICATIONS |
| ISSN: | 2041-1723 |
| Popis: | Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss. Here, we identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ in osteoclasts. We note that ELMO1 SNPs associate with bone abnormalities in humans, and that ELMO1 deletion in mice reduces bone loss in four in vivo models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. Our transcriptomic analyses coupled with CRISPR/Cas9 genetic deletion identify Elmo1 associated regulators of osteoclast function, including cathepsin G and myeloperoxidase. Further, we define the ‘ELMO1 interactome’ in osteoclasts via proteomics and reveal proteins required for bone degradation. ELMO1 also contributes to osteoclast sealing zone on bone-like surfaces and distribution of osteoclast-specific proteases. Finally, a 3D structure-based ELMO1 inhibitory peptide reduces bone resorption in wild type osteoclasts. Collectively, we identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to osteoporosis and arthritis. Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink