Abstract
Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. Depending on the phenotypic heterogeneity of monocyte/macrophage precursors and the extracellular milieu, two distinct morphological and functional cell types can arise mature OCs and giant cells (GCs). Despite their biological relevance in several physiological and pathological responses, many gaps exist in our understanding of their formation and role in bone, including the molecular determinants of cell fusion and multinucleation. Here, we outline fusogenic molecules during M-FM involved in OCs and GCs formation in healthy conditions and during OP and RA. Moreover, we discuss the impact of the inflammatory milieu on modulating macrophages phenotype and their differentiation towards mature cells. Methodological approach envisaged searches on Scopus, Web of Science Core Collection, and EMBASE databases to select relevant studies on M-FM, osteoclastogenesis, inflammation, OP, and RA. This review intends to give a state-of-the-art description of mechanisms beyond osteoclastogenesis and M-FM, with a focus on OP and RA, and to highlight potential biological therapeutic targets to prevent extreme bone loss.
Highlights
Bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA), are an enormous burden for the healthcare system worldwide, mainly due to the enhanced risk for bone fractures [1]
RANKL-Nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) signalling activates B lymphocyte-induced maturation protein 1 (Blimp1), which acts as a transcriptional repressor of anti-osteoclastogenic genes such as Irf8, Mafb, BCL6 [33] and induces various OCs genes like dendritic cell-specific transmembrane protein (DC-STAMP), ATPase H1 transporting V0 subunit d isoform 2 (ATP6V0d2), tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and NFATc1 [34]. miRNAs are small non-coding RNA, which regulate several genes at the post-transcriptional level, including those involved in OCs differentiation and fusion [35,36,37]
The macrophage multinucleation could be a biological target being a phenomenon perturbed in bone and inflammatory disorders, thereby opening valuable therapeutic insights in both RA and OP
Summary
Bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA), are an enormous burden for the healthcare system worldwide, mainly due to the enhanced risk for bone fractures [1]. In RA, the hyperproduction of inflammatory cytokines and matrix-degrading enzymes from activated immune cells in the synovial membrane contributes to driving joint destruction, including subchondral bone loss [3]. Besides their role in the immune system, many inflammatory cytokines modulate OCs recruitment and differentiation and OBs activity, leading to lower bone formation at sites of bone erosion [4,5]. We discuss challenges and prospects to improve therapeutic alternatives for OP and RA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
