HDAC inhibitors restore osteoimmune balance and bone regeneration via selective MAPK modulation in inflammatory bone disease.

backgroundInflammatory bone diseases are characterized by persistent immune activation and progressive bone destruction, posing significant barriers to spontaneous repair. Current treatments for inflammatory bone diseases seldom achieve both inflammation control and bone regeneration, underscoring the need for dual-action strategies. Epigenetic regulation via histone deacetylases (HDACs) has emerged as a pivotal mechanism linking immune responses to osteogenesis. In this study, we evaluated the therapeutic potential of the HDAC inhibitors Trichostatin A (TSA), PXD-101 (PXD), and MGCD-0103 (MGCD) to suppress inflammation, promote bone regeneration, and elucidate the underlying molecular mechanisms.

methodsThe osteoimmunomodulatory effects of three HDAC inhibitors, Trichostatin A(TSA), PXD-101 (PXD), and MGCD-0103 (MGCD), were investigated under lipopolysaccharide (LPS)-induced inflammatory conditions. RAW264.7 and MC3T3-E1 cells were co-cultured under LPS stimulation and osteogenic differentiation was induced. Macrophage polarization, cytokine secretion, osteogenic differentiation, and MAPK signaling were analyzed by qPCR, ELISA, western blotting, alkaline phosphatase and Alizarin Red S staining. In vivo, an LPS-induced calvarial osteolysis model was established in male C57BL/6 mice, and TSA, PXD, or MGCD was locally administered after significant bone erosion. Bone resorption, new bone formation, and macrophage polarization were evaluated by micro-computed tomography and immunohistochemistry.

resultsTSA, PXD, and MGCD promoted M2 macrophage polarization, suppressed pro-inflammatory cytokine production, and restored osteogenic differentiation under inflammatory conditions. These effects were mediated by selective modulation of the MAPK pathway, whereby inhibition of LPS-induced NF-κB/p38/JNK phosphorylation and enhancement of ERK activation generated a pro-regenerative osteoimmune microenvironment. In vivo, HDAC inhibitor treatment significantly shifted macrophage polarization toward M2 dominance, reduced bone resorption, and promoted new bone formation.

conclusionsTSA, PXD, and MGCD function as dual-action therapeutics by regulating macrophage polarization and enhancing osteogenesis, thereby establishing a pro-regenerative microenvironment and reversing inflammatory bone loss. These findings provide mechanistic insight into the epigenetic control of immune-bone crosstalk and support a drug-repurposing strategy that utilizes clinically available HDAC inhibitors to accelerate the development of osteoimmunomodulatory therapies.