Mechanisms by which kidney-tonifying Chinese herbs inhibit osteoclastogenesis: Emphasis on immune cells

Abstract

The immune system plays a crucial role in regulating osteoclast formation and function and has significance for the occurrence and development of immune-mediated bone diseases. Kidney-tonifying Chinese herbs, based on the theory of traditional Chinese medicine (TCM) to unify the kidney and strengthen the bone, have been widely used in the prevention and treatment of bone diseases. The common botanical drugs are tonifying kidney-yang and nourishing kidney-yin herbs, which are divided into two parts: one is the compound prescription of TCM, and the other is the single preparation of TCM and its active ingredients. These botanical drugs regulate osteoclastogenesis directly and indirectly by immune cells, however, we have limited information on the differences between the two botanical drugs in osteoimmunology. In this review, the mechanism by which kidney-tonifying Chinese herbs inhibiting osteoclastogenesis was investigated, emphasizing the immune response. The differences in the mechanism of action between tonifying kidney-yang herbs and nourishing kidney-yin herbs were analysed, and the therapeutic value for immune-mediated bone diseases was evaluated.

Keywords: immune cells; kidney-tonifying Chinese herbs; nourishing kidney-yin herbs; osteoclasts; tonifying kidney-yang herbs.

FIGURE 1

Schematic diagram of the interaction between immune cells and osteoclasts (OCs). Various immune cells and secreted cytokines act on OCs and osteoblasts (OBs) to maintain bone homeostasis on the bone surface. Th-cell subsets (Th1, Th2, Th17, Treg) play an important role in modulating the differentiation and maturation of OCs. Th1 cells secrete IFN-γ, IL-2, TNF-α and RANKL and Th2 cells secrete IL-4, IL-10, and IL-13 to regulate osteoclastogenesis. Th17 cells secrete IL-17, RANKL and TNF-α to enhance OC differentiation and bone resorption. CD4⁺ Tregs promote the bone formation and secrete CTLA-4, TGF-β, IL-10 and IL-4 to promote apoptosis and inhibit bone resorption. CD8⁺ Tregs secrete IFN-γ to inhibit the formation of the actin ring and OC activity. However, B cells secrete OPG and RANKL to regulate bone health. The two subtypes (M1 and M2) of macrophages (Mφs) differentiate into OC and secrete cytokines to regulate osteoclastogenesis. Monocytes (Mo), dendritic cells (DC) and neutrophils and cytokines are associated with OC formation and function. Pre-OCs are derived from monocytes/macrophages and differentiate into mature OCs under stimulation with M-CSF and RANKL. RANKL induces the receptor RANK on the OC surface, which recruits TRAF6 to activate downstream pathways and transcription factors. OC precursors fuse into multinucleated cells and then secrete H+, TRAP, MMP, and CTSK to absorb bone on the bone surface. Pre-OBs are derived from mesenchymal precursors and differentiate into mature OBs, which support bone formation on the bone surface.

FIGURE 2

Schematic diagram of immunoregulation mechanisms of kidney-tonifying herbs on inhibiting osteoclastogenesis. Kidney-tonifying herbs inhibit Th1, Th2, Th17, BMSC and related cytokines and activate Th1, Treg, BMSC and related cytokines to suppress the RANKL/RANK, NF-κB, MAPK, AKT, JAK/STAT signalling pathways, transcription factors NFATc1, c-Fos, and OC genes, which play a role in OC formation and function. Blue represents tonifying kidney-yang botanical drugs, while green represents nourishing kidney-yin botanical drugs. Arrows (↓) indicate positive impact, while inverted Ts (⊥) indicate negative impact.