Pyroptosis in bone loss

Abstract

Pyroptosis could be responsible for the bone loss from bone metabolic diseases, leading to the negative impact on people's health and life. It has been shown that osteoclasts, osteoblasts, macrophages, chondrocytes, periodontal and gingival cells may be involved in bone loss linked with pyroptosis. So far, the involved mechanisms have not been fully elucidated. In this review, we introduced the related cells involved in the pyroptosis associated with bone loss and summarized the role of these cells in the bone metabolism during the process of pyroptosis. We also discuss the clinical potential of targeting mechanisms in the osteoclasts, osteoblasts, macrophages, chondrocytes, periodontal and gingival cells touched upon pyroptosis to treat bone loss from bone metabolic diseases as well as the challenges of avoiding potential side effects and producing efficient treatment methods.

Keywords: Bone loss; Inflammasome; NLRP3; Osteoclast; Pyroptosis.

Fig.1

Pyroptosis modulates the activities of osteoclasts, osteoblasts, macrophages, chondrocytes, and periodontal ligament cells to play a non-negligible role in bone loss. In the canonical pathway, after exposure to PAMP and DAMP, NLRP3 inflammasome is activated and followed by the recruitment of ASC and pro-caspase-1, subsequently producing the pro-inflammatory cytokines IL-1β and IL-18. The activation mediated by aging, infection, estrogen deficiency or inflammatory condition of TLR or TNFR prompts NF-kB signaling, causing increased expression of NLRP3, pro-IL-1β, and pro-IL-18. In the noncanonical pathway, caspase-4/-5/-11 is activated upon binding to LPS of Gram-negative bacteria. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain which anchors in the cell membrane and results in cell rupture as well as the efflux of K + . In the process of pyroptosis, inflammasomes facilitate osteoclast activities and thus improve the bone resorption ability of osteoclasts. Osteoblasts, chondrocytes, periodontal ligament cells, and macrophages can elevate osteoclast activity in the context of inflammasome activation, meanwhile, the decreased osteoblast activity and increased pyroptosis of osteoblasts and periodontal ligament cells can directly upregulate bone loss and inflammation

Fig. 2

The pyroptosis related to the osteoclasts in the process of bone loss is affected by the regulation on different targets of actions. Exposure to PAMPs or DAMPs and then influenced by NF-κB, the NLRP3 inflammasome complex assemblies and activates caspase-1 and subsequently results in the cleavage of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain that anchors in the cell membrane, leading to the cell rupture. Signals from bone matrix [66], exosomes from derived MSCs [67], glyburide [71], and MCC950 [67, 68] have been developed in the presented pathway targeting NLRP3. Meanwhile, RANKL, IL-1β, and Smad3 are also the target of action to be regulated to affect bone loss involved in pyroptosis, which can be modulated by Aa [74], UA [75], Auranofin [76] or Alendronate [77], respectively. The factors that promote pyroptosis are indicated in green and pyroptosis-suppressor factors are indicated in pink as well as factors that can have both effects are indicated in brown

Fig.3

The pyroptosis related to the osteoblasts in the process of bone loss is affected by the regulation on different targets of actions. Exposure to PAMPs or DAMPs and then influenced by NF-κB, the NLRP3 inflammasome complex assemblies and activates caspase-1 and subsequently results in the cleavage of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain that anchors in the cell membrane, leading to the cell rupture. Wnt/β-catenin signaling [98], IL-17 [97], IL-18BP [52], MCC950 [99], TXNIP [89], shRNA [85] and ROS that could be inhibited by N-acetyl-L-cysteine [99], have been developed in the presented pathway targeting NLRP3. Meanwhile, NF-κB, LPS and caspase-1 are also the target of action to be regulated by PKR [103], Necrosulfonamide [102], high glucose [101] or IL-18BP [52], affecting bone loss involved in pyroptosis. The factors that promote pyroptosis are indicated in green and pyroptosis-suppressor factors are indicated in pink as well as factors that can have both effects are indicated in brown

Fig.4

Different targets of action are regulated to affect the pyroptosis related to the macrophages in the process of bone loss. Influenced by NF-κB, the NLRP3 inflammasome complex assemblies and activates caspase-1 and subsequently results in the cleavage of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain that anchors in the cell membrane, leading to the cell rupture. MARK4 [117], mycoplasma salivarium [118], staphylococcus aureus [119], and porphyromonas gingivalis [116] have been found in the presented pathway positively targeting NLRP3 to facilitate pyroptosis, yet glyburide [120], dioscin [91], metformin [121], resveratrol [122] target to suppress NLRP3. Meanwhile, caspase-1 is also the target of action to be modulated by P2X7/AMPK/cyclic stretch [124, 125] and DEX [126], cranberry PACs [127], affecting bone loss involved in pyroptosis. And NF-κB signaling is repressed by PUN [128] and cyclic stretch induced exosomes from human PDLCs [129]. The factors that promote pyroptosis are indicated in green and pyroptosis-suppressor factors are indicated in pink

Fig.5

Different targets of action are regulated to affect the pyroptosis related to the chondrocytes in the process of bone loss. Exposure to PAMPs or DAMPs and then influenced by NF-κB, the NLRP3 inflammasome complex assemblies and activates caspase-1 and subsequently results in the cleavage of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain that anchors in the cell membrane, leading to the cell rupture. Loganin [138], morroniside [139], Nrf2/HO-1 induced by Lico A (Licochalcone A) [140], and microRNA-326 delivered by BMSC-derived exosomes [141], have been developed in the presented pathway targeting NF-κB signaling, and P2X7 directly targeted the crosstalk between NF-κB and NLRP3 [142]. Meanwhile, NLRP3 are also the target of action to be regulated by Ca²⁺ [143] and icariin [144], affecting bone loss involved in pyroptosis. The factors that promote pyroptosis are indicated in green and pyroptosis-suppressor factors are indicated in pink

Fig.6

Different targets of action are regulated to affect the pyroptosis related to the periodontal and gingival cells in the process of bone loss. Exposure to PAMPs or DAMPs and then influenced by NF-κB, the NLRP3 inflammasome complex assemblies and activates caspase-1 and subsequently results in the cleavage of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 and caspase-4/-5/-11 cleave GSDMD into a GSDMD-N-terminal domain that anchors in the cell membrane, leading to the cell rupture. Periodontal bacteria [39] including porphyromonas gingivalis [13] and ED-71 [151] have been found in the presented pathway targeting LPS. Meanwhile, NLRP3 and GSDMD are also the target of action to be regulated through cyclic stretch [152, 153], and Caspase-1 as well as IL-1β are negatively targeted by VX765 [154], affecting bone loss involved in pyroptosis. The factors that promote pyroptosis are indicated in green and pyroptosis-suppressor factors are indicated in pink