CCR5 deficiency in aged mice causes a decrease in bone mass
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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.
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.
참고문헌 (28)
- Feng X, "Disorders of bone remodeling", Annu Rev Pathol, 6, pp.121~145 (2011)[DOI]
- G. A. Rodan, "Bone homeostasis", Proceedings of the National Academy of Sciences, 95(23), pp.13361~13362 (1998), Proceedings of the National Academy of Sciences[DOI]
- Nakashima T, "New insights into osteoclastogenic signaling mechanisms", Trends Endocrinol Metab, 23, pp.582~590 (2012)[DOI]
- Samantha J. Allen, "Chemokine:Receptor Structure, Interactions, and Antagonism", Annual Review of Immunology, 25(1), pp.787~820 (2007), Annual Reviews[DOI]
- P. M. Murphy, "International Union of Pharmacology. XXX. Update on Chemokine Receptor Nomenclature", Pharmacological Reviews, 54(2), pp.227~229 (2002), American Society for Pharmacology & Experimental Therapeutics (ASPET)[DOI]
- Nomiyama H, "Human CC chemokine liver-expressed chemokine", CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes, 2001, pp.13, 1021~1029
- Wanghua Gong, "Monocyte Chemotactic Protein-2 Activates CCR5 and Blocks CD4", CCR5-mediated HIV-1 Entry, Journal of Biological Chemistry, pp.1998, 273(8)[DOI]
- Tatjana Dragic, "HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5", Nature, 381(6584), pp.667~673 (1996), Springer Science and Business Media LLC[DOI]
- Repik A, "The promise of CCR5antagonists as new therapies for HIV-1", Curr Opin Investig Drugs, 8, pp.130~139 (2007)
- Ravindra K. Gupta, "HIV-1 remission following CCR5Δ32", Δ32 haematopoietic stem-cell transplantation, 2019, pp.568(7751), 244~248[DOI]
- Juan J. Gomez-Reino, "Association of rheumatoid arthritis with a functional chemokine receptor, CCR5", Arthritis & Rheumatism, 42(5), pp.989~992 (1999), Wiley[DOI]
- Arberas H, "In vitro effects of the CCR5 inhibitor maraviroc on human T cell function", J Antimicrob Chemother, 68, pp.577~586 (2013)[DOI]
- Cornu TI, "Editing CCR5 : a novel approach to HIV gene therapy", Adv Exp Med Biol, 848, pp.117~130 (2015)[DOI]
- I. Andrade, "CCR5 down-regulates osteoclast function in orthodontic tooth movement", Journal of Dental Research, 88(11), pp.1037~1041 (2009), SAGE Publications[DOI]
- Ji-Won Lee, "The HIV co-receptor CCR5 regulates osteoclast function", Nature Communications, 8(1), pp.2226~ (2017), Springer Science and Business Media LLC[DOI]
- Kristofer Wintges, "Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5)", Journal of Bone and Mineral Research, 28(10), pp.2070~2080 (2013), Wiley[DOI]
- C. Cooper, "Hip fractures in the elderly: A world-wide projection", Osteoporosis International, 2(6), pp.285~289 (1992), Springer Science and Business Media LLC[DOI]
- Sulagna Dutta, "Men and mice: Relating their ages", Life Sciences, 152, pp.244~248 (2016), Elsevier BV[DOI]
- Fatima Barmania, "C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection", Applied & Translational Genomics, 2, pp.3~16 (2013), Elsevier BV[DOI]
- "About Lulu and Nana: twin girls born healthy after gene surgery as single-cell embryos" (2018)[URL]
- Mary T. Joy, "CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury", Cell, 176(5), pp.1143-57.e1~ (2019), Elsevier BV[DOI]
- Junfeng Li, "Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt", β-catenin signaling in mice, 2017, pp.35(4), 812~819[DOI]
- Atum M Buo, "Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function", Journal of Bone and Mineral Research, 32(8), pp.1727~1738 (2017), Wiley[DOI]
- Dongsu Park, "Endogenous Bone Marrow MSCs Are Dynamic, Fate-Restricted Participants in Bone Maintenance and Regeneration", Cell Stem Cell, 10(3), pp.259~272 (2012), Elsevier BV[DOI]
- Kyung-Rok Yu, "Aging-Related Genes in Mesenchymal Stem Cells: A Mini-Review", Gerontology, 59(6), pp.557~563 (2013), S. Karger AG[DOI]
- Joseph Rucker, "Regions in β-Chemokine Receptors CCR5 and CCR2b That Determine HIV-1 Cofactor Specificity", Cell, 87(3), pp.437~446 (1996), Elsevier BV[DOI]
- Young-Yun Kong, "Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand", Nature, 402(6759), pp.304~309 (1999), Springer Science and Business Media LLC[DOI]
- Stefan Dehmel, "Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft outcome", European Journal of Immunology, 40(1), pp.267~278 (2010), Wiley[DOI]