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. 2024 Mar 5;15:1333086. doi: 10.3389/fimmu.2024.1333086

Figure 1.

Figure 1

Molecular mechanisms of TLR4 in osteoporosis development. Multifactorial proteins and signaling cascades-mediated by TLR4 are involved in osteoporosis development. Various molecules directly or indirectly involve TLR4-mediated bone remodeling process via cross-talking interaction. For example, E3 ubiquitin ligase CUL4A promotes osteoclast differentiation by upregulating ZEB1 to repress miR-340-5p expression, causing HMGB1 upregulation and the TLR4 activation. Circ_0134944/miR-630 and miR-137/KDM4A elevate the TLR4 expression, together contribute to the pathophysiologic mechanism of osteoporosis. TLR4 induces osteoblast dysfunction by inhibiting the expression of RUNX2 and activating the S100B/ERK signaling pathway. TLR4/MyD88/NF-κB signaling induces the production of multiple proinflammatory cytokines, i.e., TNF-α, IL-1, and IL-6. TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa B MyD88, Myeloid differentiation primary response gene 88; ERK, Extracellular regulated protein kinases; RANKL, Nuclear factor-kappaB ligand; CUL4A, Cullin 4 A HMGB1, High mobility group box 1; Runx2, Runt-related transcription factor 2; KDM4A, Lysine-specific demethylase 4a.