Abstract
Bone homeostasis is a metabolic balance between the new bone formation by osteoblasts and old bone resorption by osteoclasts. Excessive osteoclastic bone resorption results in low bone mass, which is the major cause of bone diseases such as rheumatoid arthritis. Small GTPases Rac1 is a key regulator of osteoclast differentiation, but its exact mechanism is not fully understood. ELMO and DOCK proteins form complexes that function as guanine nucleotide exchange factors for Rac activation. Here, we report that ELMO1 plays an important role in differentiation and bone resorption of osteoclasts. Osteoclast precursors derived from bone marrow monocytes (BMMs) of Elmo1–/– mice display defective adhesion and migration during differentiation. The cells also have a reduced activation of Rac1, p38, JNK, and AKT in response to RANKL stimulation. Importantly, we show that bone erosion is alleviated in Elmo1–/– mice in a rheumatoid arthritis mouse model. Taken together, our results suggest that ELMO1, as a regulator of Rac1, regulates osteoclast differentiation and bone resorption both in vitro and in vivo.
Highlights
Bone homeostasis is a metabolic balance between the formation and resorption of the bone in which osteoblasts and osteoclasts play crucial roles, respectively
To examine whether ELMO1 is involved in osteoclast differentiation, osteoclast precursors were cultured with macrophage colony-stimulating factor (M-CSF) and Receptor activator of NF-kB ligand (RANKL) and stained for tartrate-resistant acid phosphatase (TRAP), a marker of mature osteoclasts
Considering the fact that RANKL may induce cell apoptosis (Bharti et al, 2004), we examined whether the defect of osteoclast differentiation in Elmo1−/− cells was a consequence of reduced cell number caused by the treatment of RANKL
Summary
Bone homeostasis is a metabolic balance between the formation and resorption of the bone in which osteoblasts and osteoclasts play crucial roles, respectively. When bone resorption goes beyond formation, the homeostasis is disrupted with the consequence of low bone mass and causing bone diseases such as rheumatoid arthritis (RA), which is characterized by the presence of inflammatory synovitis accompanied by bone destruction mainly caused by osteoclasts. Derived from BMM lineage cells, osteoclast precursors differentiate into osteoclasts under the regulation of two cytokines, namely, macrophage colony-stimulating factor (M-CSF) and Receptor activator of NF-kB ligand (RANKL). Association of RANKL with its receptor RANK triggers the signal transduction pathways to induce the differentiation of osteoclast precursors to giant multinucleated osteoclasts, which play a major role in the degradation and resorption of the bone matrix (Lee and States, 2000; Lee et al, 2018).
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