P2X4 promotes interleukin‑1β production in osteoarthritis via NLRP1

Fan,Changchun; Zhao,Xuechun; Guo,Xiaofan; Cao,Xuecheng; Cai,Jinfang

doi:10.3892/mmr.2013.1748

P2X4 promotes interleukin‑1β production in osteoarthritis via NLRP1

Authors:
- Changchun Fan
- Xuechun Zhao
- Xiaofan Guo
- Xuecheng Cao
- Jinfang Cai
View Affiliations

Affiliations: Department of Orthopedic Surgery, The General Hospital of Jinan Military Command, Jinan, Shandong 250031, P.R. China, Department of Orthopedic Surgery, The Third Hospital of Jinan, Jinan, Shandong 250021, P.R. China, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: October 22, 2013 https://doi.org/10.3892/mmr.2013.1748
Pages: 340-344

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Interleukin‑1β (IL‑1β) has a significant role in osteoarthritis (OA). The purinergic receptor, P2X4, has previously been implicated in IL‑1β secretion. The NLRP1 inflammasome mediates the production of IL‑1β in inflammatory disorders. However, it is unknown whether P2X4 modulates NLRP1‑mediated IL‑1β release. In the present study, the correlation between the P2X4 receptor and NLRP1 was investigated in OA fibroblast‑like synoviocytes (OAFLS). The expression of P2X4 and NLRP1 was detected in the OAFLS. The OAFLS were stimulated with P2X4 and the levels of IL‑1β and matrix metalloproteinases (MMPs) were measured. To determine whether P2X4 is involved in NLRP1‑triggered IL‑1β production, NLRP1 small interfering RNA (siRNA) was used. In the OAFLS, a markedly higher expression of P2X4 and NLRP1 was revealed compared with that in the normal FLS. OAFLS stimulated by P2X4 resulted in concentration‑dependent increases in the production of IL‑1β, MMP‑3 and MMP‑9. Furthermore, P2X4‑mediated IL‑1β production was attenuated by the NLRP1 siRNA. The results of the present study indicate that P2X4 induced IL‑1β, MMP‑3 and MMP‑9 production in the OAFLS. IL‑1β induced by P2X4 is mediated via NLRP1. P2X4/NLRP1 may be important in the pathogenesis of OA and may represent a novel therapeutic target.

View Figures

View References

1	Peat G, McCarney R and Croft P: Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis. 60:91–97. 2011. View Article : Google Scholar : PubMed/NCBI
2	Clouet J, Vinatier C, Merceron C, Pot-vaucel M, Maugars Y, Weiss P, Grimandi G and Guicheux J: From osteoarthritis treatments to future regenerative therapies for cartilage. Drug Discov Today. 14:913–925. 2009. View Article : Google Scholar : PubMed/NCBI
3	Wright AA, Cook C and Abbott JH: Variables associated with the progression of hip osteoarthritis: a systematic review. Arthritis Rheum. 61:925–936. 2009. View Article : Google Scholar : PubMed/NCBI
4	Pap T, Müller-Ladner U, Gay RE and Gay S: Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2:361–367. 2000. View Article : Google Scholar : PubMed/NCBI
5	Mor A, Abramson SB and Pillinger MH: The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol. 115:118–128. 2005. View Article : Google Scholar : PubMed/NCBI
6	Dinarello CA: A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol. 41:1203–1217. 2011.
7	Jotanovic Z, Mihelic R, Sestan B and Dembic Z: Role of interleukin-1 inhibitors in osteoarthritis: an evidence-based review. Drugs Aging. 29:343–358. 2012. View Article : Google Scholar : PubMed/NCBI
8	Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J, Cavlar T and Hornung V: Inflammasomes: current understanding and open questions. Cell Mol Life Sci. 68:765–783. 2011. View Article : Google Scholar : PubMed/NCBI
9	Martinon F, Burns K and Tschopp J: The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 10:417–426. 2002. View Article : Google Scholar : PubMed/NCBI
10	Ray K: Crystal arthritis: NLRP3 inflammasome mediates crystal-induced joint inflammation and dysfunction. Nat Rev Rheumatol. 7:6842011. View Article : Google Scholar : PubMed/NCBI
11	Mathews RJ, Robinson JI, Battellino M, Wong C and Taylor JC; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Eyre S, Churchman SM, Wilson AG, Isaacs JD, et al: Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis. Aug 16–2013.(Epub ahead of print).
12	Sakaki H, Fujiwaki T, Tsukimoto M, Kawano A, Harada H and Kojima S: P2X4 receptor regulates P2X7 receptor-dependent IL-1β and IL-18 release in mouse bone marrow-derived dendritic cells. Biochem Biophys Res Commun. 432:406–411. 2013.PubMed/NCBI
13	Uzan B, Ea HK, Launay JM, Garel JM, Champy R, Cressent M and Lioté F: A critical role for adrenomedullin-calcitonin receptor-like receptor in regulating rheumatoid fibroblast-like synoviocyte apoptosis. J Immunol. 176:5548–5558. 2006. View Article : Google Scholar : PubMed/NCBI
14	Lioté F, Champy R, Moenner M, Boval-Boizard B and Badet J: Elevated angiogenin levels in synovial fluid from patients with inflammatory arthritis and secretion of angiogenin by cultured synovial fibroblasts. Clin Exp Immunol. 132:163–168. 2003.PubMed/NCBI
15	Alqallaf SM, Evans BA and Kidd EJ: Atypical P2X receptor pharmacology in two human osteoblast-like cell lines. Br J Pharmacol. 156:1124–1135. 2009. View Article : Google Scholar : PubMed/NCBI
16	Klein K, Aeschlimann A, Jordan S, Gay R, Gay S and Sprott H: ATP induced brain-derived neurotrophic factor expression and release from osteoarthritis synovial fibroblasts is mediated by purinergic receptor P2X4. PLoS One. 7:e366932012. View Article : Google Scholar : PubMed/NCBI
17	Ulmann L, Hirbec H and Rassendren F: P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J. 29:2290–2300. 2010. View Article : Google Scholar : PubMed/NCBI
18	Troeberg L and Nagase H: Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta. 1824:133–145. 2012. View Article : Google Scholar : PubMed/NCBI
19	Li H, Li L, Min J, Yang H, Xu X, Yuan Y and Wang D: Levels of metalloproteinase (MMP-3, MMP-9), NF-kappaB ligand (RANKL), and nitric oxide (NO) in peripheral blood of osteoarthritis (OA) patients. Clin Lab. 58:755–762. 2012.PubMed/NCBI
20	Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, McFann KK, Holland PJ, Fain PR, Dinarello CA and Spritz RA: NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proc Natl Acad Sci USA. 110:2952–2956. 2013.PubMed/NCBI
21	van de Veerdonk FL, Netea MG, Dinarello CA and Joosten LA: Inflammasome activation and IL-1β and IL-18 processing during infection. Trends Immunol. 32:110–116. 2011.
22	Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, et al: NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 37:1009–1023. 2012. View Article : Google Scholar : PubMed/NCBI
23	Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S and Sandrin-Garcia P: Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity. 45:271–278. 2012. View Article : Google Scholar : PubMed/NCBI
24	Sui J, Li H, Fang Y, Liu Y, Li M, Zhong B, Yang F, Zou Q and Wu Y: NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum. 64:647–654. 2012. View Article : Google Scholar : PubMed/NCBI