Crandall CJ, Larson JC, LaCroix AZ, Robbins JA, Wactawski-Wende J, Johnson KC et al (2021) Risk of subsequent fractures in postmenopausal women after nontraumatic vs traumatic fractures. JAMA Intern Med 181:1055–1063. https://doi.org/10.1001/jamainternmed.2021.2617

Article  PubMed  PubMed Central  Google Scholar 

Sahbani K, Shultz LC, Cardozo CP, Bauman WA, Tawfeek HA (2021) Absence of αβ T cells accelerates disuse bone loss in male mice after spinal cord injury. Ann N Y Acad Sci 1487:43–55. https://doi.org/10.1111/nyas.14518

Article  CAS  PubMed  Google Scholar 

Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J et al (2000) Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106:1229–1237. https://doi.org/10.1172/JCI11066

Article  CAS  PubMed  PubMed Central  Google Scholar 

Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G et al (2001) Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci U S A 98:13960–13965. https://doi.org/10.1073/pnas.251534698

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL (2000) TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106:1481–1488. https://doi.org/10.1172/JCI11176

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adamopoulos IE, Chao C-C, Geissler R, Laface D, Blumenschein W, Iwakura Y et al (2010) Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther 12:R29. https://doi.org/10.1186/ar2936

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yu M, Pal S, Paterson CW, Li J-Y, Tyagi AM, Adams J et al (2021) Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells. J Clin Invest 131(e143137):143137. https://doi.org/10.1172/JCI143137

Article  PubMed  Google Scholar 

Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M et al (2014) Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-α antibodies. J Bone Miner Res 29:1981–1992. https://doi.org/10.1002/jbmr.2228

Article  CAS  PubMed  Google Scholar 

Choi Y, Woo KM, Ko SH, Lee YJ, Park SJ, Kim HM et al (2001) Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8(+) T cells. Eur J Immunol 31:2179–2188

Article  CAS  PubMed  Google Scholar 

John V, Hock JM, Short LL, Glasebrook AL, Galvin RJ (1996) A role for CD8+ T lymphocytes in osteoclast differentiation in vitro. Endocrinology 137:2457–2463. https://doi.org/10.1210/endo.137.6.8641199

Article  CAS  PubMed  Google Scholar 

Jonsson AH, Zhang F, Dunlap G, Gomez-Rivas E, Watts GFM, Faust HJ et al (2022) Granzyme K+ CD8 T cells form a core population in inflamed human tissue. Sci Transl Med 14:eabo0686. https://doi.org/10.1126/scitranslmed.abo0686

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E et al (2021) Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54:99-115.e12. https://doi.org/10.1016/j.immuni.2020.11.005

Article  CAS  PubMed  Google Scholar 

Joeckel LT, Wallich R, Martin P, Sanchez-Martinez D, Weber FC, Martin SF et al (2011) Mouse granzyme K has pro-inflammatory potential. Cell Death Differ 18:1112–1119. https://doi.org/10.1038/cdd.2011.5

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jiang Z, Qi G, He X, Yu Y, Cao Y, Zhang C et al (2024) Ferroptosis in osteocytes as a target for protection against postmenopausal osteoporosis. Adv Sci (Weinh). https://doi.org/10.1002/advs.202307388

Article  PubMed  PubMed Central  Google Scholar 

Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A et al (2019) Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 20:163–172. https://doi.org/10.1038/s41590-018-0276-y

Article  CAS  PubMed  PubMed Central  Google Scholar 

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R (2018) Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36:411–420. https://doi.org/10.1038/nbt.4096

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gijón MA, Spencer DM, Siddiqi AR, Bonventre JV, Leslie CC (2000) Cytosolic phospholipase A2 is required for macrophage arachidonic acid release by agonists that do and do not mobilize calcium: novel role of mitogen-activated protein kinase pathways in cytosolic phospholipase A2 regulation. J Biol Chem 275:20146–20156. https://doi.org/10.1074/jbc.M908941199

Article  PubMed  Google Scholar 

Weitzmann MN, Pacifici R (2006) Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 116:1186–1194. https://doi.org/10.1172/JCI28550

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cline-Smith A, Axelbaum A, Shashkova E, Chakraborty M, Sanford J, Panesar P et al (2020) Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res 35:1174–1187. https://doi.org/10.1002/jbmr.3966

Article  CAS  PubMed  Google Scholar 

Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A et al (2015) A bone anabolic effect of RANKL in a murine model of osteoporosis mediated through FoxP3+ CD8 T cells. J Bone Miner Res 30:1508–1522. https://doi.org/10.1002/jbmr.2472

Article  CAS  PubMed  Google Scholar 

Zhao T, Zhang H, Guo Y, Fan Z (2007) Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. J Biol Chem 282:12104–12111. https://doi.org/10.1074/jbc.M611006200

Article  CAS  PubMed  Google Scholar 

Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H et al (2007) Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ 14:489–499. https://doi.org/10.1038/sj.cdd.4402040

Article  CAS  PubMed  Google Scholar 

Sharma M, Merkulova Y, Raithatha S, Parkinson LG, Shen Y, Cooper D et al (2016) Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1. FEBS J 283:1734–1747. https://doi.org/10.1111/febs.13699

Article  CAS  PubMed  Google Scholar 

Bouwman AC, van Daalen KR, Crnko S, ten Broeke T, Bovenschen N (2021) Intracellular and extracellular roles of Granzyme K. Front Immunol 12:677707. https://doi.org/10.3389/fimmu.2021.677707

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cooper DM, Pechkovsky DV, Hackett TL, Knight DA, Granville DJ (2011) Granzyme K activates protease-activated receptor-1. PLoS ONE 6:e21484. https://doi.org/10.1371/journal.pone.0021484

Article  CAS  PubMed  PubMed Central  Google Scholar 

Song SJ, Pagel CN, Campbell TM, Pike RN, Mackie EJ (2005) The role of protease-activated receptor-1 in bone healing. Am J Pathol 166:857–868. https://doi.org/10.1016/S0002-9440(10)62306-1

Article  CAS  PubMed  PubMed Central