Abstract
Inflammatory diseases have a negative impact on bone homeostasis via exacerbated local and systemic inflammation. Bone resorbing osteoclasts are mainly derived from hematopoietic precursors and bone marrow monocytes. Induced osteoclastogenesis during inflammation, autoimmunity, metabolic diseases, and cancers is associated with bone loss and osteoporosis. Proinflammatory cytokines, pathogen-associated molecular patterns, or endogenous pathogenic factors induce osteoclastogenic differentiation by binding to the Toll-like receptor (TLR) family expressed on surface of osteoclast precursors. As a non-canonical member of the TLRs, radioprotective 105 kDa (RP105 or CD180) and its ligand, myeloid differentiation protein 1 (MD1), are involved in several bone metabolic disorders. Reports from literature had demonstrated RP105 as an important activator of B cells, bone marrow monocytes, and macrophages, which regulates inflammatory cytokines release from immune cells. Reports from literature had shown the association between RP105 and other TLRs, and the downstream signaling mechanisms of RP105 with different “signaling-competent” partners in immune cells during different disease conditions. This review is focused to summarize: (1) the role of RP105 on immune cells’ function and inflammation regulation (2) the potential regulatory roles of RP105 in different disease-mediated osteoclast activation and the underlying mechanisms, and (3) the different “signaling-competent” partners of RP105 that regulates osteoclastogenesis.
Highlights
Osteoclasts, multinucleated bone-resorbing cells, are required for bone remodeling
Anti-CD79 reduces inflammation and improves synovial hyperplasia as well as bone and cartilage destruction (Kim et al, 2019). These results suggest that RP105 could be a biomarker in predicting the occurrence and development of rheumatoid arthritis
In the MD-1 knockout mice, sodium/calcium exchanger 1 and phosphorylation of ryanodine receptor 2 expression resulted in increased myocardial fibrosis and inflammation, proving that MD-1 regulates the activation of the TLR4/CaMKII signaling in vivo and in vitro (Shuai et al, 2020)
Summary
Osteoclasts, multinucleated bone-resorbing cells, are required for bone remodeling. Osteoclasts originate from embryonic erythromyeloid progenitors, bone marrow hematopoietic stem cells, and mononuclear precursors, which are usually present in peripheral circulation and bone marrow (Takayanagi, 2007; McGrath et al, 2015). The binding of RP105 to MD-1 results in the activation of B cells, DCs, monocytes, and macrophages, and these RP105/MD1-mediated phenomena enhance upon LPS stimulation (Schultz and Blumenthal, 2017) This phenomenon could be responsible for excessive osteoclastogenesis and bone loss in inflammatory diseases. RP105 negatively regulates TLR4-mediated IFN-β expression (Okamoto N. et al, 2017), signaling elements such as p38MAPK (Kikuchi et al, 2018), kinase phosphorylation levels of c-Jun/AP1 (Dong et al, 2019) and Akt (Yu et al, 2015), and production of proinflammatory cytokines such as IL-6 (Wezel et al, 2016), IL1β (Chen et al, 2019), and TNF-α (Louwe et al, 2014; CarrerasGonzalez et al, 2018). Ca2+ pathway, PI3K-Akt pathway, and crosstalk with NF-κB pathway Akt-PI3K and NF-κB pathway JAK/STAT and PI3K-Akt pathway Ca2+ pathway Ca2+ pathway; Akt-PI3K pathway; MAPKs pathway (MyD88-independent signaling); NF-κB pathway (MyD88-independent signaling)
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