Table 1 Potential therapeutics for endochondral ossification, including inhibitors and drugs targeting NF-κB-related signalling pathways
Inhibitors | Target | Target tissue | Main findings | Reference |
|---|---|---|---|---|
Metformin | AMPK/SIRT1 | Macrophages of HO rat | Activate AMPK or SIRT1 to block NF-κB activity, thus decreasing the secretion of inflammatory cytokines, preventing the infiltration, activation, and polarization of M1 macrophages and promoting M2 polarization. | |
Quercetin | SIRT1 | Macrophages and mast cells of HO mice | Activate SIRT1 to downregulate acetylated NF-κb p65, thereby inhibiting the transition from monocyte to macrophages and mast cells, the polarization of M1 and M2 subtypes and mast cell activity. | [23] |
ECF | SIRT1 | Macrophages of HO mice | Activate SIRT1 to downregulate acetylated NF-κb p65, thereby inhibiting macrophage polarization, infiltration and inflammatory cytokine secretion. | [24] |
Palovarotene (FDA approved) | Smad pathway | Macrophages and MSC/TSCs of FOP rats/Humans | Decrease Id1, smad5, Sox9, Runx2, OCN and p65 expression; inhibit the binding of Smad1/5/8 and Smad4 to suppress the overactivation of NF-κb, eventually suppressing osteoblast differentiation and macrophage accumulation. | [127] |
Pyrrolidinedithiocarbamate (PDTC) | NOS (Nitrous Oxide System) | Tendons of HO mice | PDTC could significantly inhibit the expression of p56 and inhibit the activity of the NF-kB pathway, significantly decreasing ectopic bone formation. | [33] |
Rapamycin | mTORC1 | Tendon cells of HO mice | Inhibit mTORC1, attenuate the progression of HO during the inflammation and early stage of chondrogenesis. Suppress early chondrogenic differentiation but promote hypertrophy and maturation at the later stage. | [62] |
BAY11-7082 | NF-κB p65 | Tendon cells of HO mice | Inhibit NF-κB, reverse the chondrogenic differentiation of TDs due to the overactivation of mTORC1 | [62] |
JSH23 | NF-κB p65 | TDSCs | Inhibit nuclear translocation of NF-κB p65, rejuvenating senescent TDSCs induced by coculture with pyroptotic macrophages and slowing osteogenic induction | [25] |
SRT1720 | SIRT1 | Macrophages and mast cells of HO mice | Activate SIRT1, decreasing the infiltration of monocyte-derived macrophages and mast cells during the early stages of HO | [23] |