The Impact of NLRP3 Inflammasome on Osteoblasts and Osteogenic Differentiation: A Literature Review

Figures & data

Figure 1 A schematic model depicting the activation process of NLRP3 inflammasome and the impact on OBs, osteogenic differentiation and osteogenic microenvironment. Various intracellular and extracellular stimuli activate NLRP3 inflammasome, leading to the release of inflammatory factors and alterations in the expression of markers associated with osteogenic differentiation. Consequently, this impedes the functionality and osteogenic differentiation capacity of OBs and their precursor cells, MSCs.

Figure 2 Potential therapeutic strategies by inhibiting NLRP3 inflammasome in OBs-related diseases.

Table 1 Therapeutic Agents Targeting NLRP3 Inflammasome in Diseases Associated with OBs and Osteogenic Differentiation

Agents		Mechanism of Action	Diseases	References
Natural compounds	ART	Enhances osteogenic differentiation and decreases the expression of genes associated with the NLRP3 inflammasome	Periodontitis	[119]
	Puerarin	Decreases the expression of osteogenic differentiation markers RUNX2 and BMP2 through targeting NLRP3	Vascular calcification	[120]
	Cardamonin	Suppresses the activation of the NLRP3 inflammasome and downregulates IL-1β expression	Vascular calcification	[121]
	BBA	Inhibits OA-associated inflammatory and catabolic processes, downregulates MAPK p38/NF-κB, NLRP3 inflammasome	OA	[122]
	Epiloliolide	Enhances human periodontal ligament cells to transform into OBs, reduces the production of pro-inflammatory mediators and cytokines by modulating the activity of NLRP3	Periodontitis	[123]
	Gallic acid	Eliminates inflammatory cytokines, NLRP3 inflammasome and facilitates the process of OBs differentiation	Periodontitis	[21]
Chemical Compounds	NAC and Mito-TEMPO	Enhances the viability of MLO-Y4 cells by inhibition of the ROS/NLRP3/Caspase-1 pathway	Bone loss	[104]
	Irisin	Suppresses the activation of the NLRP3 inflammasome and inhibits the apoptosis of OBs	OP	[82]
	Compound 17	Promotes the expression of OBs differentiation-related genes and inhibits the formation of the NLRP3 inflammasome	Inflammatory osteolysis	[124]
	CAPE	Decreases osteogenic gene/protein expression through the inhibition of NLRP3 inflammasome activation	Vascular calcification	[125]
Clinical Medication	Amitriptyline	Reduces the expression of NLRP3 in OBs	OA	[126]
	Naloxone and Thalidomide	Downregulates the NLRP3 inflammasome pathway in joint primary OA cells, including OBs	OA	[127]
	Melatonin	Enhances OBs differentiation through regulating Wnt/β-catenin signaling and the inhibition of NLRP3 inflammasome	OP	[18]
	AR/PCC	Alleviates the abnormal activation of OBs pyroptosis in the by reducing the elevated expressions of NLRP3	OP	[128]
Inhibitors	NSA	Increases the activity of ALP and the mRNA expression of differentiation-related genes in OBs	Bone fracture	[84]
	Ac-YVAD-cmk	Hinders the activation of NLRP3 and restores the viability of OBs	Osteomyelitis	[129]
	INF 39	Promotes OBs differentiation via inhibiting NLRP3	OP	[130]
	CY-09/MCC950	Specific NLRP3 inflammasome inhibitors	OP/Vascular calcification/Periodontitis	[20,67,72]
	ALP inhibitor	Decreases ALP activity and NLRP3, leading to an inhibition of the osteogenic differentiation of VICs	Vascular calcification	[131]

Wang Z, Feng X, Zhang G, et al. Artesunate ameliorates ligature-induced periodontitis by attenuating NLRP3 inflammasome-mediated osteoclastogenesis and enhancing osteogenic differentiation. Int Immunopharmacol. 2023;123:110749. doi:10.1016/j.intimp.2023.110749

 PubMed Web of Science ®Google Scholar

Liu H, Zhang X, Zhong X, et al. Puerarin inhibits vascular calcification of uremic rats. Eur J Pharmacol. 2019;855:235–243. doi:10.1016/j.ejphar.2019.05.023

 PubMed Web of Science ®Google Scholar

Wang C, Xia Y, Qu L, Liu Y, Liu X, Xu K. Cardamonin inhibits osteogenic differentiation of human valve interstitial cells and ameliorates aortic valve calcification via interfering in the NF-κB/NLRP3 inflammasome pathway. Food Funct. 2021;12(23):11808–11818. doi:10.1039/D1FO00813G

 PubMed Web of Science ®Google Scholar

Franco-Trepat E, Alonso-Pérez A, Guillán-Fresco M, et al. β boswellic acid blocks articular innate immune responses: an in silico and in vitro approach to traditional medicine. Antioxidants. 2023;12(2):371. doi:10.3390/antiox12020371

 Web of Science ®Google Scholar

Kim EN, Nabende WY, Jeong H, Hahn D, Jeong GS. The marine-derived natural product epiloliolide isolated from sargassum horneri regulates NLRP3 via PKA/CREB, promoting proliferation and anti-inflammatory effects of human periodontal ligament cells. Mar Drugs. 2021;19(7):388. doi:10.3390/md19070388

 PubMed Web of Science ®Google Scholar

Pham TH, Kim EN, Trang NM, Jeong GS. Gallic acid induces osteoblast differentiation and alleviates inflammatory response through GPR35/GSK3β/β-catenin signaling pathway in human periodontal ligament cells. J Periodontal Res. 2023;59(1):204–219. doi:10.1111/jre.13208

 PubMed Web of Science ®Google Scholar

Zhang Y, Yan M, Shan W, et al. Bisphenol A induces pyroptotic cell death via ROS/NLRP3/Caspase-1 pathway in osteocytes MLO-Y4. Food Chem Toxicol. 2022;159:112772. doi:10.1016/j.fct.2021.112772

 PubMed Web of Science ®Google Scholar

Xu L, Shen L, Yu X, Li P, Wang Q, Li C. Effects of irisin on osteoblast apoptosis and osteoporosis in postmenopausal osteoporosis rats through upregulating Nrf2 and inhibiting NLRP3 inflammasome. Exp Ther Med. 2020;19(2):1084–1090. doi:10.3892/etm.2019.8313

 PubMed Web of Science ®Google Scholar

Chen Y, Hu W, Wang Y, et al. A selected small molecule prevents inflammatory osteolysis through restraining osteoclastogenesis by modulating PTEN activity. Clin transl med. 2020;10(8):e240. doi:10.1002/ctm2.240

 PubMed Web of Science ®Google Scholar

Liu M, Li F, Huang Y, et al. Caffeic acid phenethyl ester ameliorates calcification by inhibiting activation of the AKT/NF-κB/NLRP3 inflammasome pathway in human aortic valve interstitial cells. Front Pharmacol. 2020;11:826. doi:10.3389/fphar.2020.00826

 PubMed Web of Science ®Google Scholar

Franco-Trepat E, Alonso-Pérez A, Guillán-Fresco M, et al. Amitriptyline blocks innate immune responses mediated by toll-like receptor 4 and IL-1 receptor: preclinical and clinical evidence in osteoarthritis and gout. Br J Pharmacol. 2022;179(2):270–286. doi:10.1111/bph.15707

 PubMed Web of Science ®Google Scholar

Franco-Trepat E, Guillán-Fresco M, Alonso-Pérez A, et al. Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells. Biomed Pharmacother. 2022;155:113671. doi:10.1016/j.biopha.2022.113671

 PubMed Web of Science ®Google Scholar

Xu L, Zhang L, Wang Z, et al. Melatonin suppresses estrogen deficiency-induced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcified Tissue Int. 2018;103(4):400–410. doi:10.1007/s00223-018-0428-y

 PubMed Web of Science ®Google Scholar

Fu F, Luo H, Du Y, et al. AR/PCC herb pair inhibits osteoblast pyroptosis to alleviate diabetes-related osteoporosis by activating Nrf2/Keap1 pathway. J Cell Mol Med. 2023;27(22):3601–3613. doi:10.1111/jcmm.17928

 PubMed Web of Science ®Google Scholar

Zhang J, Wei K. Necrosulfonamide reverses pyroptosis-induced inhibition of proliferation and differentiation of osteoblasts through the NLRP3/caspase-1/GSDMD pathway. Exp Cell Res. 2021;405(2):112648. doi:10.1016/j.yexcr.2021.112648

 PubMed Web of Science ®Google Scholar

Greene E, Flees J, Dhamad A, et al. Double-stranded RNA is a novel molecular target in osteomyelitis pathogenesis: a translational avian model for human bacterial chondronecrosis with osteomyelitis. Am J Pathol. 2019;189(10):2077–2089. doi:10.1016/j.ajpath.2019.06.013

 PubMed Web of Science ®Google Scholar

Chen W, Tang P, Fan S, Jiang X. A novel inhibitor INF 39 promotes osteogenesis via blocking the NLRP3/IL-1β axis. Biomed Res Int. 2022;2022:7250578. doi:10.1155/2022/7250578

 PubMed Web of Science ®Google Scholar

Lu J, Xie S, Deng Y, Xie X, Liu Y. Blocking the NLRP3 inflammasome reduces osteogenic calcification and M1 macrophage polarization in a mouse model of calcified aortic valve stenosis. Atherosclerosis. 2022;347:28–38. doi:10.1016/j.atherosclerosis.2022.03.005

 PubMed Web of Science ®Google Scholar

Liu S, Du J, Li D, et al. Oxidative stress induced pyroptosis leads to osteogenic dysfunction of MG63 cells. J Mol Histol. 2020;51(3):221–232. doi:10.1007/s10735-020-09874-9

 PubMed Web of Science ®Google Scholar

Guo L, Zhang Y, Liu H, Cheng Q, Yang S, Yang D. All-trans retinoic acid inhibits the osteogenesis of periodontal ligament stem cells by promoting IL-1β production via NF-κB signaling. Int Immunopharmacol. 2022;108:108757. doi:10.1016/j.intimp.2022.108757

 PubMed Web of Science ®Google Scholar

Zhang C, Liu M, Wang X, et al. ALP inhibitors inhibit inflammatory responses and osteoblast differentiation in hVIC via AKT-ERK pathways. Alternat Therap Health Med. 2023;29(1):58–65.

 PubMed Web of Science ®Google Scholar