Targeted disruption of adenosine kinase in myeloid monocyte cells increases osteoclastogenesis and bone resorption in mice

Ye,Qiuying; Li,Ge; Liu,Shuhua; Guan,Yalun; Li,Yunfeng; Li,Jinling; Jia,Huanhuan; Li,Xuejiao; Li,Qingnan; Huang,Ren; Wang,Hui; Zhang,Yu

doi:10.3892/ijmm.2018.3394

Targeted disruption of adenosine kinase in myeloid monocyte cells increases osteoclastogenesis and bone resorption in mice

Authors:
- Qiuying Ye
- Ge Li
- Shuhua Liu
- Yalun Guan
- Yunfeng Li
- Jinling Li
- Huanhuan Jia
- Xuejiao Li
- Qingnan Li
- Ren Huang
- Hui Wang
- Yu Zhang
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Affiliations: Department of Food and Drugs, Qingyuan Polytechnic, Qingyuan, Guangdong 511510, P.R. China, Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, Guangdong 510663, P.R. China
Published online on: January 17, 2018 https://doi.org/10.3892/ijmm.2018.3394
Pages: 2177-2184

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Abstract

Adenosine kinase (ADK) serves an important role in intracellular adenosine clearance via phosphorylating adenosine to AMP. The role of adenosine and its receptors in the maintenance of bone homeostasis is well studied, particularly in osteoclastogenesis and bone resorption; however, the function of ADK in bone metabolism is still unclear. In the present study, utilizing the cre/floxp recombination system, mice with conditional loss of ADK function in myeloid monocyte cells were used to assess the effect of ADK deficiency on bone metabolism. Mice were evaluated by means of gross observation and bone histomorphometric analysis. Ex vivo osteoclast differentiation and bone resorption were also examined using genetic deletion and pharmacologic inhibition of ADK in osteoclasts. Compared with control mice, the results of the present study demonstrate that adult mice lacking ADK in the myeloid monocyte cells had reduced body weight and nasoanal length. The results of bone histomorphometric analysis revealed that bone mass was significantly decreased and osteoclastic parameters were increased in the study mice. Furthermore, in vitro cell culture revealed that inhibition of ADK function promoted osteoclast differentiation and bone resorption. Osteoclast‑associated gene expression, including tartrate‑resistant acid phosphatase, nuclear factor of activated T‑cells, cytoplasmic 1, matrix metalloproteinase 9, Cathepsin K and calcitonin receptor, was also significantly increased. These results suggest that mice with ADK deficiency have reduced bone formation due to increased osteoclastogenesis and bone resorption. The present study provides further insight into the mechanism by which ADK serves a key role in bone metabolism.

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1	Boison D: Adenosine kinase: Exploitation for therapeutic gain. Pharmacol Rev. 65:906–943. 2013. View Article : Google Scholar : PubMed/NCBI
2	Andres CM and Fox IH: Purification and properties of human placental adenosine kinase. J Biol Chem. 254:11388–11393. 1979.PubMed/NCBI
3	Antonioli L, Blandizzi C, Pacher P and Haskó G: Immunity, inflammation and cancer: A leading role for adenosine. Nat Rev Cancer. 13:842–857. 2013. View Article : Google Scholar : PubMed/NCBI
4	Boison D: The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol. 84:249–262. 2008. View Article : Google Scholar : PubMed/NCBI
5	Lusardi TA, Lytle NK, Szybala C and Boison D: Caffeine prevents acute mortality after TBI in rats without increased morbidity. Exp Neurol. 234:161–168. 2012. View Article : Google Scholar : PubMed/NCBI
6	Pignataro G, Simon RP and Boison D: Transgenic overexpression of adenosine kinase aggravates cell death in ischemia. J Cereb Blood Flow Metab. 27:1–5. 2007. View Article : Google Scholar
7	Pawelczyk T, Sakowicz M, Szczepanska-Konkel M and Angielski S: Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats. Arch Biochem Biophys. 375:1–6. 2000. View Article : Google Scholar : PubMed/NCBI
8	Giglioni S, Leoncini R, Aceto E, Chessa A, Civitelli S, Bernini A, Tanzini G, Carraro F, Pucci A and Vannoni D: Adenosine kinase gene expression in human colorectal cancer. Nucleosides Nucleotides Nucleic Acids. 27:750–754. 2008. View Article : Google Scholar : PubMed/NCBI
9	Raggatt LJ and Partridge NC: Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 285:25103–25108. 2010. View Article : Google Scholar : PubMed/NCBI
10	Mediero A and Cronstein BN: Adenosine and bone metabolism. Trends Endocrinol Metab. 24:290–300. 2013. View Article : Google Scholar : PubMed/NCBI
11	He W, Mazumder A, Wilder T and Cronstein BN: Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma. FASEB J. 27:3446–3454. 2013. View Article : Google Scholar : PubMed/NCBI
12	He W and Cronstein BN: Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling. Purinergic Signal. 8:327–337. 2012. View Article : Google Scholar : PubMed/NCBI
13	Mediero A, Kara FM, Wilder T and Cronstein BN: Adenosine A2A receptor ligation inhibits osteoclast formation. Am J Pathol. 180:775–786. 2012. View Article : Google Scholar :
14	Corciulo C, Wilder T and Cronstein BN: Adenosine A2B receptors play an important role in bone homeostasis. Purinergic Signal. 12:537–547. 2016. View Article : Google Scholar : PubMed/NCBI
15	Rath-Wolfson L, Bar-Yehuda S, Madi L, Ochaion A, Cohen S, Zabutti A and Fishman P: IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Clin Exp Rheumatol. 24:400–406. 2006.PubMed/NCBI
16	Staufner C, Lindner M, Dionisi-Vici C, Freisinger P, Dobbelaere D, Douillard C, Makhseed N, Straub BK, Kahrizi K, Ballhausen D, et al: Adenosine kinase deficiency: Expanding the clinical spectrum and evaluating therapeutic options. J Inherit Metab Dis. 39:273–283. 2016. View Article : Google Scholar
17	Boison D, Scheurer L, Zumsteg V, Rülicke T, Litynski P, Fowler B, Brandner S and Mohler H: Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proc Natl Acad Sci USA. 99:6985–6990. 2002. View Article : Google Scholar : PubMed/NCBI
18	Massaro EJ and Rogers JM: The Skeleton: Biochemical, Genetic, and Molecular Interactions in Development and Homeostasis. Humana Press; Totowa, NJ: 2004, View Article : Google Scholar
19	Sandau US, Colino-Oliveira M, Jones A, Saleumvong B, Coffman SQ, Liu L, Miranda-Lourenço C, Palminha C, Batalha VL, Xu Y, et al: Adenosine kinase deficiency in the brain results in maladaptive synaptic plasticity. J Neurosci. 36:12117–12128. 2016. View Article : Google Scholar : PubMed/NCBI
20	Clausen BE, Burkhardt C, Reith W, Renkawitz R and Förster I: Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8:265–277. 1999. View Article : Google Scholar
21	Takahashi N, Udagawa N, Tanaka S and Suda T: Generating murine osteoclasts from bone marrow. Methods Mol Med. 80:129–144. 2003.PubMed/NCBI
22	Tevlin R, McArdle A, Chan CK, Pluvinage J, Walmsley GG, Wearda T, Marecic O, Hu MS, Paik KJ, Senarath-Yapa K, et al: Osteoclast derivation from mouse bone marrow. J Vis Exp. 6:e520562014.
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
24	Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR and Parfitt AM: Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry nomenclature committee. J Bone Miner Res. 28:2–17. 2013. View Article : Google Scholar :
25	Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S, Brandberg G, Halldin M, Falkenberg M, Jakobs C, et al: Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet. 89:507–515. 2011. View Article : Google Scholar : PubMed/NCBI
26	Boyle WJ, Simonet WS and Lacey DL: Osteoclast differentiation and activation. Nature. 423:337–342. 2003. View Article : Google Scholar : PubMed/NCBI
27	Albers J, Keller J, Baranowsky A, Beil FT, Catala-Lehnen P, Schulze J, Amling M and Schinke T: Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin. J Cell Biol. 200:537–549. 2013. View Article : Google Scholar : PubMed/NCBI
28	Bartell SM, Kim HN, Ambrogini E, Han L, Iyer S, Serra Ucer S, Rabinovitch P, Jilka RL, Weinstein RS, Zhao H, et al: FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H₂O₂ accumulation. Nat Commun. 5:37732014. View Article : Google Scholar
29	Kim HN, Han L, Iyer S, de Cabo R, Zhao H, O'Brien CA, Manolagas SC and Almeida M: Sirtuin1 suppresses osteoclastogenesis by deacetylating FoxOs. Mol Endocrinol. 29:1498–1509. 2015. View Article : Google Scholar : PubMed/NCBI
30	Sun W, Zhao C, Li Y, Wang L, Nie G, Peng J, Wang A, Zhang P, Tian W, Li Q, et al: Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. Cell Discov. 2:160152016. View Article : Google Scholar : PubMed/NCBI
31	Young JD, Yao SY, Sun L, Cass CE and Baldwin SA: Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica. 38:995–1021. 2008. View Article : Google Scholar : PubMed/NCBI
32	Kara FM, Chitu V, Sloane J, Axelrod M, Fredholm BB, Stanley ER and Cronstein BN: Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J. 24:2325–2333. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kara FM, Doty SB, Boskey A, Goldring S, Zaidi M, Fredholm BB and Cronstein BN: Adenosine A(1) receptors regulate bone resorption in mice: Adenosine A(1) receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A(1) receptor-knockout mice. Arthritis Rheum. 62:534–541. 2010. View Article : Google Scholar : PubMed/NCBI
34	Carroll SH, Wigner NA, Kulkarni N, Johnston-Cox H, Gerstenfeld LC and Ravid K: A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J Biol Chem. 287:15718–15727. 2012. View Article : Google Scholar : PubMed/NCBI
35	Gharibi B, Abraham AA, Ham J and Evans BA: Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J Bone Miner Res. 26:2112–2124. 2011. View Article : Google Scholar : PubMed/NCBI
36	Hinton DJ, McGee-Lawrence ME, Lee MR, Kwong HK, Westendorf JJ and Choi DS: Aberrant bone density in aging mice lacking the adenosine transporter ENT1. PLoS One. 9:e888182014. View Article : Google Scholar : PubMed/NCBI
37	Tsuchiya A, Kanno T, Saito M, Miyoshi Y, Gotoh A, Nakano T and Nishizaki T: Intracellularly transported adenosine induces apoptosis in (corrected) MCF-7 human breast cancer cells by accumulating AMID in the nucleus. Cancer Lett. 321:65–72. 2012. View Article : Google Scholar : PubMed/NCBI
38	Hiken JF and Steinberg TH: ATP downregulates P2X7 and inhibits osteoclast formation in RAW cells. Am J Physiol Cell Physiol. 287:C403–C412. 2004. View Article : Google Scholar : PubMed/NCBI
39	Paschou SA, Dede AD, Anagnostis PG, Vryonidou A, Morganstein D and Goulis DG: Type 2 diabetes and osteoporosis: A guide to optimal management. J Clin Endocrinol Metab. 102:3621–3634. 2017. View Article : Google Scholar : PubMed/NCBI
40	Hegazy SK: Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab. 33:207–212. 2015. View Article : Google Scholar
41	Montagnani A, Gonnelli S, Alessandri M and Nuti R: Osteoporosis and risk of fracture in patients with diabetes: An update. Aging Clin Exp Res. 23:84–90. 2011. View Article : Google Scholar : PubMed/NCBI
42	Lee YS, Kim YS, Lee SY, Kim GH, Kim BJ, Lee SH, Lee KU, Kim GS, Kim SW and Koh JM: AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts. Bone. 47:926–937. 2010. View Article : Google Scholar : PubMed/NCBI
43	Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD and Bai XC: Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem. 112:2902–2909. 2011. View Article : Google Scholar : PubMed/NCBI
44	McCarthy AD, Cortizo AM and Sedlinsky C: Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes. 7:122–133. 2016. View Article : Google Scholar : PubMed/NCBI