ELMO1 signaling is a promoter of osteoclast function and bone loss

Sanja Arandjelovic,Laura S Shankman,Ming Zhou,Suna Onengut-Gumuscu,Justin S A Perry,Adam Ceroi,Kodi S Ravichandran,Igor Smirnov,Dirk Elewaut,Isabelle Cambré,Thomas P Conrads,Scott F Walk

doi:10.1038/s41467-021-25239-6

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.

Highlights

Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss
We observed a significant correlation between single-nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes with various bone and joint abnormalities in humans (Fig. 1a and Supplementary Table 1)
Microcomputed tomography (MicroCT)-based comparison of the vertebral trabecular bone content and density in those littermate mice that reached 1 year of age showed that the trabecular bone loss that was observed in Elmo1+/−Opg−/− mice was reduced in Elmo1−/−Opg−/− mice (Fig. 1e, top panels), evidenced by the increased trabecular number and reduced spacing between the trabeculae (Fig. 1e, bottom panels)

Summary

Introduction

Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss. We identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to osteoporosis and arthritis. The cytoplasmic adapter protein ELMO1 was originally identified as a component of the machinery that facilitates phagocytosis of apoptotic cells, from nematodes to humans[5,6]. In this context, ELMO1 was shown to associate with DOCK and RAC proteins to mediate cytoskeletal reorganization leading to corpse uptake[5,6]. We show that ELMO1 acts as a signaling hub affecting the function of osteoclasts, cells that mediate bone degradation, to promote bone loss in arthritis and osteoporosis

Methods

Results

Conclusion