Monocytes from male patients with ankylosing spondylitis display decreased osteoclastogenesis and decreased RANKL/OPG ratio
The present study investigates the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) in male patients with ankylosing spondylitis (AS). We demonstrated that monocytes from these patients display a lower capacity to generate osteoclasts compared to cells from healthy controls, and osteoclastogenesis was negatively correlated with disease duration.
Ankylosing spondylitis (AS) is a disease characterized by new bone growth that leads to syndesmophyte formation but AS patients frequently present with low bone mineral density/fractures. Osteoclastogenesis in AS patients is poorly studied and controversial. The aim of this study is to determine if the osteoclastogenic capacity of PBMCs is different in AS patients compared to controls and the relationship between osteoclastogenesis and clinical/laboratory parameters.
PBMCs from 85 male AS patients and 59 controls were tested for CD16+ cells and induced to differentiate into osteoclasts over 3 weeks in vitro. Serum levels of RANKL, osteoprotegerin (OPG), C-terminal telopeptide of type I collagen (CTX), and amino-terminal pro-peptide of type I collagen (P1NP) were also evaluated.
PBMCs from AS patients had fewer CD16+ cells and produced fewer osteoclasts compared to controls. Apoptosis occurred less frequently in osteoclasts obtained from AS patients than in osteoclasts from the controls. A lower RANKL/OPG and CTX/P1NP were observed in AS patients compared to controls. AS patients taking NSAIDs presented no difference regarding the number of OCs produced and the percentage of CD16+ cells compared to controls. However, patients taking TNF inhibitors (TNFi) presented lower OC numbers than controls. A negative correlation was demonstrated between the number of osteoclasts generated from PBMCs of AS patients and disease duration.
Monocytes from male AS patients display a lower capacity to generate osteoclasts in vitro compared to cells from controls. Osteoclastogenesis was negatively correlated with disease duration. This finding supports the idea that osteoclasts play a role in the physiopathology of bone disease in AS patients.
KeywordsAnkylosing spondylitis Apoptosis CTX Osteoclastogenesis Osteoprotegerin P1NP RANKL
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) #2011/23781-2 and Conselho Nacional de Ciência e Tecnologia (CNPQ) #301805/2013-0 (RMRP).
Compliance with ethical standards
This study was approved by the Local Ethics Committee on Human Research at the Sao Paulo University-CAPPesq 0061/11.
Conflicts of interest
Valeria F. Caparbo, Carla GS Saad, Julio CB Moares, Artur J de Brum-Fernandes, and Rosa MR Pereira declare no conflicts of interest and no competing financial interests.
- 2.Sprangers S, de Vries TJ, Everts V (2016) Review article: monocyte heterogeneity: consequences for monocyte-derived immune cells. J Immunol Res 1475435Google Scholar
- 15.Perpétuo IP, Raposeiro R, Caetano-Lopes J, Vieira-Sousa E, Campanilho-Marques R, Ponte C, Canhão H, Ainola M, Fonseca JE (2015) Effect of tumor necrosis factor inhibitor therapy on osteoclasts precursors in ankylosing spondylitis. PLoS One (10, 12):e0144655Google Scholar
- 17.Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, Dougados M, Hermann KG, Landewé R, Maksymowych W, van der Heijde (2009) The assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 68(Suppl 2):ii1–i44CrossRefPubMedGoogle Scholar
- 21.Durand M, Boire G, Komarova SV, Dixon SJ, Sims SM, Harrison RE, Nabavi N, Maria O, Manolson MF, Mizianty M, Kurgan L, de Brum-Fernandes AJ (2011) The increased in vitro osteoclastogenesis in patients with rheumatoid arthritis is due to increased percentage of precursors and decreased apoptosis—the In Vitro Osteoclast Differentiation in Arthritis (IODA) study. Bone 48(3):588–596CrossRefPubMedGoogle Scholar
- 22.Durand M, Komarova SV, Bhargava A, Dixon SJ, Sims SM, Harrison RE, Nabavi N, Maria O, Manolson MF, Mizianty M, Kurgan L, de Brum-Fernandes AJ (2013) Monocytes from patients with osteoarthritis display increased osteoclastogenesis and bone resorption: the In Vitro Osteoclast Differentiation in Arthritis study. Arthritis Rheum 65(1):148–158CrossRefPubMedGoogle Scholar
- 25.MCculluch CE, Searle SR (2001) Generalized, linear and mixed models. Wiley, New YorkGoogle Scholar
- 27.Webers C, Essers I, Ramiro S, Stolwijk C, Landewé R, van der Heijde D, van den Bosch F, Dougados M, van Tubergen A (2016) Gender-attributable differences in outcome of ankylosing spondylitis: long-term results from the Outcome in Ankylosing Spondylitis International Study. Rheumatology (Oxford) 55(3):419–428Google Scholar
- 29.Chen CH, Chen HA, Liao HT, Liu CH, Tsai CY, Chou CT (2010) Soluble receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin in ankylosing spondylitis: OPG is associated with poor physical mobility and reflects systemic inflammation. Clin Rheumatol 29(10):1155–1161CrossRefPubMedGoogle Scholar
- 34.van der Weijden MA, Claushuis TA, Nazari T, Lems WF, Dijkmans BA, van der Horst-Bruinsma IE (2012) High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol 31(11):1529–1535CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Francois RJ, Neure L, Sieper J, Braun J (2006) Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumor necrosis factor a in two patients with early disease and transforming growth factor b in three more advanced cases. Ann Rheum Dis 65:713–720CrossRefPubMedGoogle Scholar
- 44.Grazio S, Kusić Z, Cvijetić S, Grubišić F, Balenović A, Nemčić T, Matijević-Mikelić V, Punda M, Sieper J (2012) Relationship of bone mineral density with disease activity and functional ability in patients with ankylosing spondylitis: a cross-sectional study. Rheumatol Int 32(9):2801–2808CrossRefPubMedGoogle Scholar
- 47.Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Märker-Hermann E, Zeidler H, Braun J, Sieper J (2012) Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis 71(10):1616–1622CrossRefPubMedGoogle Scholar