Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Osteoporosis International
Published in: Osteoporosis International 7/2017

01-07-2017 | Original Article

Evidence that activation of ASIC1a by acidosis increases osteoclast migration and adhesion by modulating integrin/Pyk2/Src signaling pathway

Authors: X. Li, J.-X. Ye, M.-H. Xu, M.-D. Zhao, F.-L. Yuan

Published in: Osteoporosis International | Issue 7/2017

Login to get access

Abstract

Summary

Activated acid-sensing ion channel 1a (ASIC1a) is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. These results indicated that ASIC1a activation by extracellular acid may cause osteoclast migration and adhesion through Ca2+-dependent integrin/Pyk2/Src signaling pathway.

Introduction

Osteoclast adhesion and migration are responsible for osteoporotic bone loss. Acidic conditions promote osteoclastogenesis. ASIC1a in osteoclasts is associated with acid-induced osteoclastogenesis through modulating transcription factor NFATc1 activation. However, the influence and the detailed mechanism of ASIC1a in regulating osteoclast adhesion and migration, in response to extracellular acid, are not well characterized.

Methods

In this study, knockdown of ASIC1a was achieved in bone marrow macrophage cells using small interfering RNA (siRNA). The adhesion and migration abilities of osteoclast precursors and osteoclasts were determined by adhesion and migration assays, in vitro. Bone resorption was performed to measure osteoclast function. Cytoskeletal changes were assessed by F-actin ring formation. αvβ3 integrin expression in osteoclasts was measured by flow cytometry. Western blotting and co-immunoprecipitation were performed to measure alterations in integrin/Pyk2/Src signaling pathway.

Results

Our results showed that blockade of ASIC1a using ASIC1a-siRNA inhibited acid-induced osteoclast precursor migration and adhesion, as well as osteoclast adhesion and bone resorption; we also demonstrated that inhibition of ASIC1a decreased the cell surface αvβ3 integrin and β3 protein expression. Moreover, blocking of ASIC1a inhibited acidosis-induced actin ring formation and reduced Pyk2 and Src phosphorylation in osteoclasts and also inhibited the acid-induced association of the αvβ3 integrin/Src/Pyk2.

Conclusion

Together, these results highlight a key functional role of ASIC1a/αvβ3 integrin/Pyk2/Src signaling pathway in migration and adhesion of osteoclasts.
Literature
1.
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381CrossRefPubMedPubMedCentral
2.
Cooper C, Campion G, Melton LJ 3rd (1992) Hip fractures in the elderly: a world-wide projection. Osteoporos Int 2:285–289CrossRefPubMed
3.
Udagawa N, Takahashi N, Jimi E et al (1999) Osteoblasts/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor: receptor activator of NF-kappa B ligand. Bone 25:517–523CrossRefPubMed
4.
Brazier H, Pawlak G, Vives V, Blangy A (2009) The Rho GTPase Wrch1 regulates osteoclast precursor adhesion and migration. Int J Biochem Cell Biol 41:1391–1401CrossRefPubMed
5.
6.
Kikuta J, Kawamura S, Okiji F, Shirazaki M, Sakai S, Saito H, Ishii M (2013) Sphingosine-1-phosphate-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D. Proc Natl Acad Sci U S A 110:7009–7013CrossRefPubMedPubMedCentral
7.
8.
Komarova SV, Pereverzev A, Shum JW, Sims SM, Dixon SJ (2005) Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Proc Natl Acad Sci U S A 102:2643–2648CrossRefPubMedPubMedCentral
9.
Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M (1997) A proton-gated cation channel involved in acid-sensing. Nature 386:173–177CrossRefPubMed
10.
Xiong ZG, Zhu XM, Chu XP et al (2004) Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118:687–698CrossRefPubMed
11.
Xiong ZG, Chu XP, Simon RP (2006) Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol 209:59–68CrossRefPubMed
12.
Hey JG, Chu XP, Seeds J, Simon RP, Xiong ZG (2007) Extracellular zinc protects against acidosis-induced injury of cells expressing Ca2+-permeable acid-sensing ion channels. Stroke 38:670–673CrossRefPubMed
13.
Duan B, Wu LJ, Yu YQ, Ding Y, Jing L, Xu L, Chen J, Xu TL (2007) Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J Neurosci 27:11139–11148CrossRefPubMed
14.
Weng XC, Zheng JQ, Li J, Xiao WB (2007) Underlying mechanism of ASIC1a involved in acidosis-induced cytotoxicity in rat C6 glioma cells. Acta Pharmacol Sin 28:1731–1736CrossRefPubMed
15.
Yuan FL, Zhao MD, Jiang DL, Jin C, Liu HF, Xu MH, Hu W, Li X (2016) Involvement of acid-sensing ion channel 1a in matrix metabolism of endplate chondrocytes under extracellular acidic conditions through NF-kappaB transcriptional activity. Cell Stress Chaperones 21:97–104CrossRefPubMed
16.
Li X, Wu FR, Xu RS, Hu W, Jiang DL, Ji C, Chen FH, Yuan FL (2014) Acid-sensing ion channel 1a-mediated calcium influx regulates apoptosis of endplate chondrocytes in intervertebral discs. Expert Opin Ther Targets 18:1–14CrossRefPubMed
17.
Li X, Xu RS, Jiang DL, He XL, Jin C, Lu WG, Su Q, Yuan FL (2013) Acid-sensing ion channel 1a is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. FEBS Lett 587:3236–3242CrossRefPubMed
18.
19.
20.
Ahn H, Kim JM, Lee K, Kim H, Jeong D (2012) Extracellular acidosis accelerates bone resorption by enhancing osteoclast survival, adhesion, and migration. Biochem Biophys Res Commun 418:144–148CrossRefPubMed
21.
Nakamura I, Duong LT, Rodan SB, Rodan GA (2007) Involvement of alpha(v)beta3 integrins in osteoclast function. J Bone Miner Metab 25:337–344CrossRefPubMed
22.
Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL, Ross FP, Swat W (2005) Vav3 regulates osteoclast function and bone mass. Nat Med 11:284–290CrossRefPubMed
23.
Novack DV, Faccio R (2011) Osteoclast motility: putting the brakes on bone resorption. Ageing Res Rev 10:54–61CrossRefPubMed
24.
Tomomura M, Hasegawa H, Suda N, Sakagami H, Tomomura A (2012) Serum calcium-decreasing factor, caldecrin, inhibits receptor activator of NF-kappaB ligand (RANKL)-mediated Ca2+ signaling and actin ring formation in mature osteoclasts via suppression of Src signaling pathway. J Biol Chem 287:17963–17974CrossRefPubMedPubMedCentral
25.
Duong LT, Lakkakorpi P, Nakamura I, Rodan GA (2000) Integrins and signaling in osteoclast function. Matrix Biol 19:97–105CrossRefPubMed
26.
27.
Pereverzev A, Komarova SV, Korcok J, Armstrong S, Tremblay GB, Dixon SJ, Sims SM (2008) Extracellular acidification enhances osteoclast survival through an NFAT-independent, protein kinase C-dependent pathway. Bone 42:150–161CrossRefPubMed
28.
Takeuchi S, Hirukawa K, Togari A (2013) Acidosis inhibits mineralization in human osteoblasts. Calcif Tissue Int 93:233–240CrossRefPubMed
29.
Hu W, Chen FH, Yuan FL, Zhang TY, Wu FR, Rong C, Jiang S, Tang J, Zhang CC, Lin MY (2012) Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury. Inflamm Res 61:327–335CrossRefPubMed
30.
Rong C, Chen FH, Jiang S, Hu W, Wu FR, Chen TY, Yuan FL (2012) Inhibition of acid-sensing ion channels by amiloride protects rat articular chondrocytes from acid-induced apoptosis via a mitochondrial-mediated pathway. Cell Biol Int 36:635–641CrossRefPubMed
31.
Yuan FL, Chen FH, Lu WG, Li X, Wu FR, Li JP, Li CW, Wang Y, Zhang TY, Hu W (2010) Acid-sensing ion channel 1a mediates acid-induced increases in intracellular calcium in rat articular chondrocytes. Mol Cell Biochem 340:153–159CrossRefPubMed
32.
33.
Zhao H, Liu X, Zou H et al (2016) Osteoprotegerin disrupts peripheral adhesive structures of osteoclasts by modulating Pyk2 and Src activities. Cell Adhes Migr 10:299–309CrossRef
34.
Jurdic P, Saltel F, Chabadel A, Destaing O (2006) Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol 85:195–202CrossRefPubMed
35.
McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440CrossRefPubMedPubMedCentral
36.
37.
Jiang H, Wang Y, Viniegra A, Sima C, McCulloch CA, Glogauer M (2015) Adseverin plays a role in osteoclast differentiation and periodontal disease-mediated bone loss. FASEB J 29:2281–2291CrossRefPubMed
38.
Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J (1995) Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 376:737–745CrossRefPubMed
39.
Duong LT, Lakkakorpi PT, Nakamura I, Machwate M, Nagy RM, Rodan GA (1998) PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. J Clin Invest 102:881–892CrossRefPubMedPubMedCentral
40.
Sanjay A, Houghton A, Neff L et al (2001) Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol 152:181–195CrossRefPubMedPubMedCentral
Metadata
Title
Evidence that activation of ASIC1a by acidosis increases osteoclast migration and adhesion by modulating integrin/Pyk2/Src signaling pathway
Authors
X. Li
J.-X. Ye
M.-H. Xu
M.-D. Zhao
F.-L. Yuan
Publication date
01-07-2017
Publisher
Springer London
Published in
Osteoporosis International / Issue 7/2017
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-017-4017-0

Other articles of this Issue 7/2017

Osteoporosis International 7/2017 Go to the issue

Original Article

Comparison of two automated assays of BTM (CTX and P1NP) and reference intervals in a Danish population

Letter

Response to Sabour: Dual-energy X-ray absorptiometry and fracture prediction in patients with spinal cord injuries and disorders: methodological issues

Original Article

Reduced bone mass and preserved marrow adipose tissue in patients with inflammatory bowel diseases in long-term remission

Original Article

Cortical microstructure compensates for smaller bone size in young Caribbean Hispanic versus non-Hispanic white men

Letter

Recommendations for the screening of adherence to oral bisphosphonates: reply to comments by Zhou and Sheng

Original Article

Hip fracture incidence and social deprivation: results from a French ecological study