Crosstalk between bone and the immune system

Abstract

Bone functions not only as a critical element of the musculoskeletal system but also serves as the primary lymphoid organ harboring hematopoietic stem cells (HSCs) and immune progenitor cells. The interdisciplinary field of osteoimmunology has illuminated the dynamic interactions between the skeletal and immune systems, vital for the maintenance of skeletal tissue homeostasis and the pathogenesis of immune and skeletal diseases. Aberrant immune activation stimulates bone cells such as osteoclasts and osteoblasts, disturbing the bone remodeling and leading to skeletal disorders as seen in autoimmune diseases like rheumatoid arthritis. On the other hand, intricate multicellular network within the bone marrow creates a specialized microenvironment essential for the maintenance and differentiation of HSCs and the progeny. Dysregulation of immune-bone crosstalk in the bone marrow environment can trigger tumorigenesis and exacerbated inflammation. A comprehensive deciphering of the complex "immune-bone crosstalk" leads to a deeper understanding of the pathogenesis of immune diseases as well as skeletal diseases, and might provide insight into potential therapeutic approaches.

Keywords: Bone; Bone marrow microenvironment; Immune system; Osteoclast; Osteoimmunology; RANKL.

Fig. 1

Critical role of RANKL in the immune organ development. RANKL plays essential roles in the development of the immune organs—bone marrow, thymus, lymph nodes and gut-associated lymphoid tissues. In each tissue formation, various cell types act as sources of RANKL expression. Regarding skeletal development and bone remodeling, the main cellular source of RANKL for osteoclast differentiation varies by life stages; hypertrophic chondrocytes and osteoblasts in fetal and neonatal stages, and osteocytes and bone marrow adipoprogenitors cells in adult stages

Fig. 2

Mechanism of bone destruction in RA. The intricate immune–bone interaction among lymphocytes, fibroblasts, osteoclasts and osteoblasts drives the bone destruction in RA. IL-17 produced by Th17 cells induces RANKL expression in synovial fibroblasts. Th17 cells induce the proinflammatory cytokines including TNF, IL-6 and IL-1, which further upregulate RANKL expression. Synovial fibroblasts in RA consist of two main types: inflammatory fibroblasts in the sublining layer and RANKL⁺ tissue-destructive fibroblasts in the lining layer. The polarization of tissue-destructive synovial fibroblasts is controlled by the transcriptional factor ETS1. The immunoglobulin immune complexes directly promote osteoclastogenesis. Desialylated immune complexes are particularly effective in this process, regulated by an IL-23–Th17 cell-dependent mechanism. TNF induces the production of Wnt inhibitors like DKK1 and sclerostin, suppressing bone formation

Fig. 3

Immune regulation by bone cells in the bone marrow microenvironment A LepR⁺CXCL12⁺ mesenchymal stem cells support HSCs by producing key factors SCF and CXCL12. LepR⁺CXCL12⁺ mesenchymal stem cells have the capacity to differentiate into osteoblasts and adipocytes in adult bone marrow, and fibrotic cells in the pathological settings. Osteoblasts maintains common lymphoid progenitors by producing IL-7 and DLL4, and plasma cells via extracellular ATP in the bone marrow. B Alterations in osteoblasts result in the development of myeloid leukemia. Activation of β-catenin and SHP2 in osteoblasts induces myeloid leukemia. Deletion of Dicer1 in osteoblasts leads to myelodysplasia and leukemia, through decreased expression of the Sbds gene, which is frequently mutated in Shwachman–Diamond syndrome. C Various body stresses, including tumors, exercise and nutrition deprivation, stimulate osteoblasts and stromal cells in the bone marrow microenvironment, resulting in altered immune cell differentiation. The effects extend to immune responses in extraskeletal tissues, influencing anti-tumor immune responses, infection protection and inflammatory responses