Abstract
Arginase 1 (Arg1) limits the availability of l-arginine for producing nitric oxide (NO) and ornithine, a substrate for polyamine synthesis. Anti-osteoclastogenic activities of NO and polyamines, and the involvement of Arg1 on the dendritic cell differentiation of dendritic cells have been reported, but the relevance of Arg1 to osteoclast differentiation has not been investigated. Here, we observed Arg1 down-regulation during the RANKL-induced differentiation of bone marrow-derived macrophages into osteoclasts. Arg1 overexpression significantly inhibited osteoclast differentiation with low NO production, while Arg1 knockdown enhanced osteoclast differentiation with high NO production. These results suggest that Arg1 and NO have reciprocal roles as negative and positive regulators, respectively, of osteoclast differentiation. We conclude that Arg1 is down-regulated during osteoclast differentiation and may negatively regulate osteoclast differentiation by regulating NO production.
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References
Boucher JL, Moali C, Tenu JP (1999) Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for l-arginine utilization. Cell Mol Life Sci 55:1015–1128
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342
Chae HJ, Park RK, Chung HT, Kang JS, Kim MS, Choi DY, Bang BG, Kim HR (1997) Nitric oxide is a regulator of bone remodelling. J Pharm Pharmacol 49:897–902
Cirelli JA, Park CH, MacKool K, Taba M Jr, Lustig KH, Burstein H, Giannobile WV (2009) AAV2/1-TNFR: Fc gene delivery prevents periodontal disease progression. Gene Ther 16:426–436
Daroszewska A, Ralston SH (2006) Mechanisms of disease: genetics of Paget’s disease of bone and related disorders. Nat Clin Pract Rheumatol 2:270–277
Herrera BS, Martins-Porto R, Maia-Dantas A, Campi P, Spolidorio LC, Costa SK, Van Dyke TE, Gyurko R, Muscara MN (2011) iNOS-derived nitric oxide stimulates osteoclast activity and alveolar bone loss in ligature-induced periodontitis in rats. J Periodontol 82:1608–1615
Iezaki T, Hinoi E, Yamamoto T, Ishiura R, Ogawa S, Yoneda Y (2012) Amelioration by the natural polyamine spermine of cartilage and bone destruction in rats with collagen-induced arthritis. J Pharmacol Sci 119:107–111
Lee SK, Huang H, Lee SW, Kim KH, Kim KK, Kim HM, Lee ZH, Kim HH (2004) Involvement of iNOS-dependent NO production in the stimulation of osteoclast survival by TNF-alpha. Exp Cell Res 298:359–368
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408
Mancini L, Becherini L, Benvenuti S, Brandi ML (1997) Bioeffects of a nitric oxide donor in a human preosteoclastic cell line. Int J Clin Pharmacol Res 17:93–96
Nilforoushan D, Gramoun A, Glogauer M, Manolson MF (2009) Nitric oxide enhances osteoclastogenesis possibly by mediating cell fusion. Nitric Oxide 21:27–36
Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, Gu K, Shah V, Pei L, Zarbo RJ, McCauley L, Shi S, Chen S, Wang CY (2007) NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13:62–69
Rauh MJ, Sly LM, Kalesnikoff J, Hughes MR, Cao LP, Lam V, Krystal G (2004) The role of SHIP1 in macrophage programming and activation. Biochem Soc Trans 32:785–788
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
Takayanagi H (2009) Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 5:667–676
Toya T, Hakuno D, Shiraishi Y, Kujiraoka T, Adachi T (2014) Arginase inhibition augments nitric oxide production and facilitates left ventricular systolic function in doxorubicin-induced cardiomyopathy in mice. Physiol Rep 2. pii: e12130. doi: 10.14814/phy2.12130
van’t Hof RJ, Macphee J, Libouban H, Helfrich MH, Ralston SH (2004) Regulation of bone mass and bone turnover by neuronal nitric oxide synthase. Endocrinology 145:5068–5074
Yamamoto T, Hinoi E, Fujita H, Iezaki T, Takahata Y, Takamori M, Yoneda Y (2012) The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br J Pharmacol 166:1084–1096
Yang Q, Wei J, Zhong L, Shi M, Zhou P, Zuo S, Wu K, Zhu M, Huang X, Yu Y, Zhang H, Yin H, Zhou J (2015) Cross talk between histone deacetylase 4 and STAT6 in the transcriptional regulation of arginase 1 during mouse dendritic cell differentiation. Mol Cell Biol 35:63–75
Yeon JT, Ryu BJ, Choi SW, Heo JC, Kim KJ, Son YJ, Kim SH (2014) Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways. Amino Acids 46:2605–2614
Zheng H, Yu X, Collin-Osdoby P, Osdoby P (2006) RANKL stimulates inducible nitric-oxide synthase expression and nitric oxide production in developing osteoclasts. An autocrine negative feedback mechanism triggered by RANKL-induced interferon-beta via NF-kappaB that restrains osteoclastogenesis and bone resorption. J Biol Chem 281:15809–15820
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This work was supported by the Korea Research Institute of Chemical Technology project grant (SI-1404).
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Handling Editor: E. Agostinelli.
J. -T. Yeon and S. -W. Choi equally contributed to this study.
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Yeon, JT., Choi, SW. & Kim, S.H. Arginase 1 is a negative regulator of osteoclast differentiation. Amino Acids 48, 559–565 (2016). https://doi.org/10.1007/s00726-015-2112-0
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DOI: https://doi.org/10.1007/s00726-015-2112-0