International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
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CCR5 deficiency in aged mice causes a decrease in bone mass

  • Oh, Eun-Ji (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Zang, Yaran (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Kim, Jung-Woo (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Lee, Mi Nam (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Song, Ju Han (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Oh, Sin-Hye (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Kwon, Seung Hee (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Yang, Jin-Woo (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Koh, Jeong-Tae (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University)
  • Received : 2019.12.02
  • Accepted : 2019.12.16
  • Published : 2019.12.31
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Abstract

The CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor that regulates chemotaxis and effector functions of immune cells. It also serves as the major co-receptor for the entry of human immunodeficiency virus (HIV). Recently, CCR5 inhibitors have been developed and used for the treatment or prevention of HIV infections. Additionally, it has been identified that CCR5 controls bone homeostasis by regulating osteoclastogenesis and the communication between osteoblasts and osteoclasts. However, the effects of CCR5 inhibition on bone tissue in elderly patients are unknown. This study aimed to examine the bone phenotype of aged CCR5 knockout (KO) mice. Femoral and tibial bones were isolated from 12-month and 18-month old wild-type (WT) and CCR5 KO mice, and microcomputed tomography and histology analyses were performed. Twelve-month-old CCR5 KO mice exhibited a decreased trabecular bone mass and cortical bone thickness in both femoral and tibial bones compared with age-matched WT mice. Eighteen-month-old mice also showed a decreased trabecular bone mass in femurs compared with control WT mice, but not in tibial bones. Unlike in 12-month-old mice, the cortical margin of femurs and tibias in 18-month-old mice were rough, likely because they were aggravated by the deficiency of CCR5. Overall, our data suggest that the deficiency of CCR5 with aging can cause severe bone loss. When CCR5 inhibitors or CCR5 inactivating technologies are used in elderly patients, a preventive strategy for bone loss should be considered.

Keywords

References

  1. Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol 2011;6:121-45. doi: 10.1146/annurevpathol-011110-130203.
  2. Rodan GA. Bone homeostasis. Proc Natl Acad Sci U S A 1998;95:13361-2. doi: 10.1073/pnas.95.23.13361.
  3. Nakashima T, Hayashi M, Takayanagi H. New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol Metab 2012;23:582-90. doi: 10.1016/j.tem.2012.05.005.
  4. Allen SJ, Crown SE, Handel TM. Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 2007;25:787-820. doi: 10.1146/annurev.immunol.24.021605.090529.
  5. Murphy PM. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol Rev 2002;54:227-9. doi: 10.1124/pr.54.2.227.
  6. Nomiyama H, Hieshima K, Nakayama T, Sakaguchi T, Fujisawa R, Tanase S, Nishiura H, Matsuno K, Takamori H, Tabira Y, Yamamoto T, Miura R, Yoshie O. Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes. Int Immunol 2001;13:1021-9. doi: 10.1093/intimm/13.8.1021.
  7. Gong W, Howard OM, Turpin JA, Grimm MC, Ueda H, Gray PW, Raport CJ, Oppenheim JJ, Wang JM. Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication. J Biol Chem 1998;273:4289-92. doi: 10.1074/jbc.273.8.4289.
  8. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996;381:667-73. doi: 10.1038/381667a0.
  9. Repik A, Richards KH, Clapham PR. The promise of CCR5 antagonists as new therapies for HIV-1. Curr Opin Investig Drugs 2007;8:130-9.
  10. Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H, Grant P, Nastouli E, Lambert J, Pace M, Salasc F, Monit C, Innes AJ, Muir L, Waters L, Frater J, Lever AML, Edwards SG, Gabriel IH, Olavarria E. HIV-1 remission following CCR5 ${\Delta}$32/${\Delta}$32 haematopoietic stem-cell transplantation. Nature 2019;568:244-8. doi: 10.1038/s41586-019-1027-4.
  11. Gomez-Reino JJ, Pablos JL, Carreira PE, Santiago B, Serrano L, Vicario JL, Balsa A, Figueroa M, de Juan MD. Association of rheumatoid arthritis with a functional chemokine receptor, CCR5. Arthritis Rheum 1999;42:989-92. doi:10.1002/1529-0131(199905)42:5<989::AID-ANR18>3.0.CO;2-U.
  12. Arberas H, Guardo AC, Bargallo ME, Maleno MJ, Calvo M, Blanco JL, Garcia F, Gatell JM, Plana M. In vitro effects of the CCR5 inhibitor maraviroc on human T cell function. J Antimicrob Chemother 2013;68:577-86. doi: 10.1093/jac/dks432.
  13. Cornu TI, Mussolino C, Bloom K, Cathomen T. Editing CCR5: a novel approach to HIV gene therapy. Adv Exp Med Biol 2015;848:117-30. doi: 10.1007/978-1-4939-2432-5_6.
  14. Andrade I Jr, Taddei SR, Garlet GP, Garlet TP, Teixeira AL, Silva TA, Teixeira MM. CCR5 down-regulates osteoclast function in orthodontic tooth movement. J Dent Res 2009;88:1037-41. doi: 10.1177/0022034509346230.
  15. Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T. The HIV co-receptor CCR5 regulates osteoclast function. Nat Commun 2017;8:2226. doi: 10.1038/s41467-017-02368-5.
  16. Wintges K, Beil FT, Albers J, Jeschke A, Schweizer M, Claass B, Tiegs G, Amling M, Schinke T. Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5). J Bone Miner Res 2013;28:2070-80. doi: 10.1002/jbmr.1937.
  17. Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992;2:285-9. doi: 10.1007/bf01623184.
  18. Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci 2016;152:244-8. doi: 10.1016/j.lfs.2015.10.025.
  19. Barmania F, Pepper MS. C-C chemokine receptor type five (CCR5): an emerging target for the control of HIV infection. Appl Transl Genom 2013;2:3-16. doi: 10.1016/j.atg.2013.05.004.
  20. About Lulu and Nana: twin girls born healthy after gene surgery as single-cell embryos [Internet]. 2018 Nov 25 [cited 2019 Apr 26]. Available from: https://www.youtube.com/watch?v=th0vnOmFltc.
  21. Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST. CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell 2019;176:1143-57.e13. doi: 10.1016/j.cell.2019.01.044.
  22. Li J, Bao Q, Chen S, Liu H, Feng J, Qin H, Li A, Liu D, Shen Y, Zhao Y, Zong Z. Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt/${\beta}$-catenin signaling in mice. J Orthop Res 2017;35:812-9. doi: 10.1002/jor.23339.
  23. Buo AM, Tomlinson RE, Eidelman ER, Chason M, Stains JP. Connexin43 and Runx2 interact to affect cortical bone geometry, skeletal development, and osteoblast and osteoclast function. J Bone Miner Res 2017;32:1727-38. doi: 10.1002/jbmr.3152.
  24. Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL, Lin CP, Kronenberg HM, Scadden DT. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012;10: 259-72. doi: 10.1016/j.stem.2012.02.003.
  25. Yu KR, Kang KS. Aging-related genes in mesenchymal stem cells: a mini-review. Gerontology 2013;59:557-63. doi:10.1159/000353857.
  26. Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, Smyth RJ, Collman RG, Broder CC, Vassart G, Doms RW, Parmentier M. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 1996;87:437-46. doi: 10.1016/s0092-8674(00)81364-1.
  27. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304-9. doi:10.1038/46303.
  28. Dehmel S, Wang S, Schmidt C, Kiss E, Loewe RP, Chilla S, Schlondorff D, Grone HJ, Luckow B. Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft outcome. Eur J Immunol 2010;40:267-78. doi: 10.1002/eji.200939652.