ELMO1 signaling is a promoter of osteoclast function and bone loss

Abstract

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.

“Genetic scissors” CRISPR/Cas9 genome editing cutting-edge biocarrier technology for bone and cartilage repair

“…Then the transfected macrophages developed functional defects. Arandjelovic et al, [ 86 ] 2021 Noggin High expression of BMP2 upregulates the expression of osteogenic genes and induces differentiation of stem cells into osteoblasts. Noggin can bind BMP2 and prevent its docking with stem cell surface receptors.…”

“…Arandjelovic et al deleted the ELMO1 gene in Hoxb8 macrophages via CRISPR/Cas9 and sgRNA. Then the transfected macrophages developed functional defects [ 86 ] ( Fig. 7 A and B).…”

Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex

“…With the world’s population aging, osteoporosis has arisen as a frequent illness that endangers human health and safety ( Wang Y. et al, 2020 ). According to the latest epidemiological survey and research, osteoporosis affects >200 million people worldwide, with women aged >50 years old accounting for >40% of the osteoporosis cases, and bone fractures occur in most of the patients ( Zhu et al, 2019 ; Arandjelovic et al, 2021 ). Adult bone homeostasis is dependent on a coordinated bone-remodeling process that comprises osteoclast-mediated bone resorption and osteoblast-mediated bone synthesis ( Zheng et al, 2020 ).…”

Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1−/−, elmo2−/−, and elmo3−/− Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins

“…ELMO3 mutations were recently suggested as the cause of developmental delay and autism in humans (Tran et al, 2021). ELMO proteins were linked to multiple other diseases, such as cancer, diabetes mellitus, inflammatory bowel disease and arthritis (Shimazaki et al, 2005;Hathaway et al, 2016;Sayed et al, 2020;Arandjelovic et al, 2021). Respective studies provided insights into the variety of the ELMO proteins' functions as promotive factors for cell growth, proliferation and metastasis in multiple human carcinomas (Peng et al, 2016;Hu et al, 2018;Pan et al, 2019).…”

“…In mouse models, ELMO1 was identified as a microbial sensor in epithelial and phagocytic cells that activates inflammatory signals and as a required factor for bacterial internalization and monocyte recruitment in inflammatory bowel disease (Sayed et al, 2020). Elmo1 −/− mouse models of osteoporosis and arthritis showed reduced bone erosion and identified ELMO1 as positive regulator of osteoclast function and bone loss (Arandjelovic et al, 2021). In addition Elmo1 was described as a promotor of angiogenesis and early vascular development in zebrafish (Epting et al, 2010;Schäker et al, 2015).…”