Abstract
Summary
The phenotypic and functional characteristics of immune cells of osteoporotic women compared to healthy controls similar for age and estrogen level showed for the first time significant changes in several B lymphocytes populations in postmenopausal osteoporosis, related to bone mineral density (BMD) and fractures, and a significant lower basal secretion of interferon-gamma (IFN-γ) by CD4+.
Introduction
To investigate the interactions between bone and immune system, we studied the phenotypic and functional characteristics of immune cells of 26 postmenopausal women with osteoporotic (OP) fractures compared to 24 healthy controls.
Methods
We analyzed surface markers of peripheral B, CD4+ and CD8+ lymphocytes and cytokine secretion in supernatants of these cells cultured with or without stimulation. Body composition was assessed by dual energy X-ray absorptiometry.
Results
The two groups were similar for age and estrogen level. OP women had a significantly lower body mass index, fat mass, and lean mass. The number of CD19+, CD19+/CD27+, CD19+/CD27+/CD5−/CD38+ and CD19+/CD27+/RANK+, CD4+/CD27+/CD45RA−/RANK+, and CD4+/CD27+/CD45RA−/CD28+ was lower in OP women and positively correlated to BMD. In OP women, under basal conditions, CD4+ secreted less IFN-γ and B lymphocytes more granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF was positively correlated to fracture rate and negatively to BMD.
Conclusions
Our results suggest that, regardless of age and estrogen status, postmenopausal OP is associated with immune changes, highlighting a possible role of IFN-γ in the pathophysiology of OP and reporting, for the first time, changes in several B lymphocyte populations. These alterations may reflect the frailty observed after fracture, providing new insight into the mechanisms of morbidity and mortality associated with OP fractures.
Similar content being viewed by others
References
Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 17:1726–33
Kado DM, Browner WS, Palermo L et al (1999) Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med. 159:1215–20
Lorenzo J, Horowitz M, Choi Y (2008) Osteoimmunology: interactions of the bone and immune system. Endocr. Rev. 29:403–40
Takayanagi H, Sato K, Takaoka A et al (2005) Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev 208:181–193
Mundy GR (2007) Osteoporosis and inflammation. Nutr. Rev. 65:S147–51
Horwood N (2008) Lymphocyte-derived cytokines in inflammatory arthritis. Autoimmunity. 41:230–8
Kong YY, Feige U, Sarosi I et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–9
Briot K, Garnero P, Le Henanff A et al (2005) Body weight, body composition, and bone turnover changes in patients with spondyloarthropathy receiving anti-tumour necrosis factor alpha treatment. Ann Rheum Dis. 64:1137–40
Visvanathan S, van der Heijde D, Deodhar A et al (2008) Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis. 68:175–82
Lorenzo JA, Naprta A, Rao Y et al (1998) Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy. Endocrinology. 139:3022–5
Poli V, Balena R, Fattori E et al (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 13:1189–96
Cenci S, Weitzmann MN, Roggia C et al (2000) Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest. 106:1229–37
Blin-Wakkach C, Wakkach A, Rochet N et al (2004) Characterization of a novel bipotent hematopoietic progenitor population in normal and osteopetrotic mice. J Bone Miner Res 19:1137–43
Li Y, Li A, Yang X et al (2007) Ovariectomy-induced bone loss occurs independently of B cells. J Cell Biochem. 100:1370–5
World Health Organization (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series. WHO, Geneva
Delmonico MJ, Harris TB, Lee JS et al (2007) Health, Aging and Body Composition Study.Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women. J Am Geriatr Soc 55:769–74
Lane NE (2006) Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 194:S3–11
Ravn P, Cizza G, Bjarnason NH et al (1999) Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group. J Bone Miner Res 14:1622–7
Martini G, Valenti R, Giovani S et al (1997) Age-related changes in body composition of healthy and osteoporotic women. Maturitas. 27:25–33
Schott AM, Cormier C, Hans D et al (1998) How hip and whole-body bone mineral density predict hip fracture in elderly women: the EPIDOS Prospective Study. Osteoporos Int. 8:247–54
Gnudi S, Sitta E, Fiumi N (2007) Relationship between body composition and bone mineral density in women with and without osteoporosis: relative contribution of lean and fat mass. J Bone Miner Metab. 25:326–32
Joseph C, Kenny AM, Taxel P et al (2005) Role of endocrine-immune dysregulation in osteoporosis, sarcopenia, frailty and fracture risk. Mol Aspects Med. 26:181–201
Walsh MC, Hunter GR, Livingstone MB (2006) Sarcopenia in premenopausal and postmenopausal women with osteopenia, osteoporosis and normal bone mineral density. Osteoporos Int. 17:61–7
Rodríguez L, Graniel J, Ortiz R (2007) Effect of leptin on activation and cytokine synthesis in peripheral blood lymphocytes of malnourished infected children. Clin Exp Immunol 148:478–85
Sansoni P, Vescovini R, Fagnoni F et al (2008) The immune system in extreme longevity. Exp Gerontol. 43:61–5
Hakim FT, Flomerfelt FA, Boyiadzis M et al (2004) Aging, immunity and cancer. Curr Opin Immunol 16:151–6
Lazuardi L, Jenewein B, Wolf AM et al (2005) Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology 114:37–43
Weitzmann MN, Pacifici R (2006) Estrogen regulation of immune cell bone interactions. Ann N Y Acad Sci. 1068:256–74
D’Amelio P, Grimaldi A, Di Bella S et al (2008) Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone. 43:92–100
Cantorna MT, Yu S, Bruce D (2008) The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med. 29:369–75
Gao Y, Grassi F, Ryan MR et al (2007) IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 117:122–32
Zheng SX, Vrindts Y, Lopez M et al (1997) Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis. Maturitas 26:63–71
Pietschmann P, Grisar J, Thien R et al (2001) Immune phenotype and intracellular cytokine production of peripheral blood mononuclear cells from postmenopausal patients with osteoporotic fractures. Exp Gerontol. 36:1749–59
Walsh MC, Kim N, Kadono Y et al (2006) Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 24:33–63
Mezquita-Raya P, De La Higuera M, Garcia DF et al (2005) The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos Int. 16:1368–1374
Stern A, Laughlin GA, Bergstrom J et al (2007) The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor kappaB legend with bone mineral density in older adults: the Rancho Bernardo study. Eur J Endocrinol. 156:555–62
Uemura H, Yasui T, Miyatani Y et al (2008) Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women. J Endocrinol Invest. 31:163–8
Imai Y, Tsunenari T, Fukase M et al (1990) Quantitative bone histomorphometry and circulating T lymphocyte subsets in postmenopausal osteoporosis. J Bone Miner Res. 5:393–9
Montecino-Rodriguez E, Dorshkind K (2006) Evolving patterns of lymphopoiesis from embryogenesis through senescence. Immunity 24:659–662
Eghbali-Fatourechi G, Khosla S, Sanyal A et al (2003) Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest. 111:1221–1230
Boyce BF, Xing L (2008) Bruton and Tec: new links in osteoimmunology. Cell Metab 7:283–5
Wu JY, Scadden DT, Kronenberg HM (2009) Role of the osteoblast lineage in the bone marrow hematopoietic niches. J Bone Miner Res 24:759–64
Acknowledgment
We would like to thank the “Programme Hospitalier de Recherche Clinique Regional du CHU de Nice,” the “Centre National de Recherche en Sciences,” Sanofi-Aventis “the alliance for bone health,” and Eli Lilly for their financial support. We would also like to thank Abdelilah Wakkach for providing technical training, Claudine Blin-Wakkach for her advice in the initial discussion, and Dr Brigitte Dunais for proofreading the manuscript.
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Table S1
(PDF 19 kb)
Rights and permissions
About this article
Cite this article
Breuil, V., Ticchioni, M., Testa, J. et al. Immune changes in post-menopausal osteoporosis: the Immunos study. Osteoporos Int 21, 805–814 (2010). https://doi.org/10.1007/s00198-009-1018-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-009-1018-7