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Osteoporosis International

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01-05-2015 | Original Article

RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus

Authors: A. C. Bonfá, L. P. C. Seguro, V. Caparbo, E. Bonfá, R. M. R. Pereira

Published in: Osteoporosis International | Issue 5/2015

Abstract

Summary

Premenopausal women with systemic lupus erythematosus (SLE) have a higher prevalence of low bone mineral density and vertebral fractures. Multiple genetic loci for osteoporotic fracture were identified in recent genome-wide association studies. This study provides a novel data demonstrating that receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) polymorphisms likely plays an important role in the bone remodeling process in SLE premenopausal women.

Introduction

The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) of the RANKL, RANK, and OPG genes in premenopausal SLE patients and their association with sRANKL and OPG serum levels, vertebral fractures, and bone mineral density (BMD).

Methods

A total of 211 premenopausal SLE patients (American College of Rheumatology (ACR) criteria) and 154 healthy controls were enrolled. SNPs of RANKL 290A>G (rs2277438), OPG 1181G>C (rs2073618), 245T>G (rs3134069), 163A>G (rs3102735), and RANK A>G (rs3018362) were obtained by real-time PCR. sRANKL/OPG serum levels were determined by ELISA. BMD and vertebral fractures were evaluated by dual-energy X-ray absorptiometry (DXA).

Results

SLE patients and controls had similar frequencies of the RANKL 290 G allele (p = 0.94), OPG 1181 C allele (p = 0.85), OPG 245 G allele (p = 0.85), OPG 163 G allele (p = 0.78), and RANK G allele (p = 0.87). Further analysis of the SLE patients revealed that the frequency of the RANKL 290 G allele was lower in patients with fractures than that in patients without fractures (28.1 vs 46.9 %, p = 0.01). In addition, the frequency of the OPG 245 G allele was higher in patients with low BMD than that in patients with normal BMD (31.4 vs 18.1 %, p = 0.04). No association of OPG 1181 G>C, OPG 163 A>G, and RANK A>G SNPs with BMD/fractures was found. Additionally, no association was observed between RANKL/OPG/RANK SNPs and sRANKL/OPG serum levels.

Conclusions

Our study provides novel data demonstrating that RANKL/OPG genetic variations appear to play a role in bone remodeling, particularly in its major complication, fracture, in premenopausal patients with SLE.

Lee C, Ramsey-Goldman R (2005) Osteoporosis in systemic lupus erythematosus mechanisms. Rheum Dis Clin North Am 31:363–385CrossRefPubMed

Sinigaglia L, Varenna M, Girasole G, Bianchi G (2006) Epidemiology of osteoporosis in in Rheumatic diseases. Rheum Dis Clin North Am 32:631–658CrossRefPubMed

Pereira RM, Carvalho JF, Canalis E (2010) Glucocorticoid-induced osteoporosis in rheumatic diseases. Clinics (Sao Paulo) 65:1197–1205CrossRef

Regio P, Bonfá E, Takayama L, Pereira R (2008) The influence of lean mass in trabecular and cortical bone in juvenile onset systemic lupus erythematosus. Lupus 17:787–792CrossRefPubMed

Sinigaglia L, Varenna M, Binelli L, Zucchi F, Ghiringhelli D, Fantini F (2000) Bone mass in systemic lupus erythematosus. Clin Exp Rheumatol 18:S27–S34

Bultink IEM, Lems WF, Kostense PJ, Dijkmans BAC, Voskuyl AE (2005) Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis & Rheumatism 54:2044–2050CrossRef

Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J (2002) Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab 87:4080–4084CrossRefPubMed

Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176CrossRefPubMed

Mencej-Bedrac S, Prezelj J, Marc J (2011) TNFRSF11B gene polymorphisms 1181G>C and 245T>G as well as haplotype CT influence bone mineral density in postmenopausal women. Maturitas 69:263–267CrossRefPubMed

10.

Bezerra MC, Carvalho JF, Prokopowitsch AS, Pereira RM (2005) RANK, RANKL and osteoprotegerin in arthritic bone loss. Braz J Med Biol Res 38:161–170CrossRefPubMed

11.

Lane NE (2006) Therapy Insight: osteoporosis and osteonecrosis in systemic lupus erythematosus. Nat Clin Pract Rheumatol 2:562–569CrossRefPubMed

12.

Bhalla AK (2010) Management of osteoporosis in a pre-menopausal woman. Best Pract Res Clin Rheumatol 24:313–327CrossRefPubMed

13.

Tan W, Wu H, Zhao J, Derber LA, Lee DM, Shadick NA et al (2010) A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis. Arthritis Rheum 62:2864–2875CrossRefPubMedCentralPubMed

14.

Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T et al (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365CrossRefPubMed

15.

Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF (2002) Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 17:1245–1255CrossRefPubMed

16.

Piedra M, García-Unzueta MT, Berja A, Paule B, Lavin BA, Valero C, Riancho JA, Amado JÁ (2011) Single nucleotide polymorphism of the OPG/RANKL system genes in primary hyperparathyroidism and their relatioship with bone mineral density. BMC Med Genet 20:168CrossRef

17.

Nguyen TV, Eisman JA (2013) Genetic profiling and individualized assessment of fracture risk. Nat Rev Endocrinol 9:153–161CrossRefPubMed

18.

Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277CrossRefPubMed

19.

Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35:630–640CrossRefPubMed

20.

Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Fortin P, Ginzler E et al (2000) The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. J Rheumatol 27:373–376PubMed

21.

Lewiecki EM, Gordon CM, Baim S, Leonard MB, Bishop NJ, Bianchi ML et al (2008) International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions. Bone 43:1115–1121CrossRefPubMed

22.

Obrant KJ, Bengnér U, Johnell O, Nilsson BE, Sernbo I (1989) Increasing age-adjusted risk of fragility fractures: a sign of increasing osteoporosis in successive generations? Calcif Tissue Int 44:157–167CrossRefPubMed

23.

Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148CrossRefPubMed

24.

Domiciano DS, Figueiredo CP, Lopes JB, Kuroishi ME, Takayama L, Caparbo VF et al (2013) Vertebral fracture assessment by dual X-ray absorptiometry: a valid tool to detect vertebral fractures in community-dwelling older adults in a population-based survey. Arthritis Care Res (Hoboken) 65:809–815CrossRef

25.

Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215CrossRefPubMedCentralPubMed

26.

Kirkwood BR, Sterne JAC (2006) Essential medical statistics, 2nd edn. Blackwell Science, Massachusetts, USA, p 502

27.

Hosmer DW, Lemeshow S (2000) Applied logistic regression, 2ath edn. Wiley, New York, p 320CrossRef

28.

Yeap SS, Fauzi AR, Kong NC, Halim AG, Soehardy Z, Rahimah S et al (2009) Influences on bone mineral density in Malaysian premenopausal systemic lupus erythematosus patients on corticosteroids. Lupus 18:178–181CrossRefPubMed

29.

Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W et al (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthr Care Res (Hoboken) 62:1515–1526CrossRef

30.

Chugh PK (2013) Management of women with systemic lupus erythematosus. Maturitas 75:207–214CrossRefPubMed

31.

Lopes JB, Fung LK, Cha CC, Gabriel GM, Takayama L, Figueiredo CP, Pereira RM (2012) The impact of asymptomatic vertebral fractures on quality of life in older community-dwelling women: the São Paulo Ageing & Health Study. Clinics (Sao Paulo) 67:1401–1406CrossRef

32.

Miyagawa H, Yamai M, Sakaguchi D, Kiyohara C, Tsukamoto H, Kimoto Y et al (2008) Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology 47:158–164CrossRefPubMed

33.

Kim JG, Kim JH, Kim JY, Ku SY, Jee BC, Suh CS, Kim SH, Choi YM (2007) Association between osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL levels, and bone mineral density in Korean postmenopausal women. Menopause 14(5):913–918CrossRefPubMed

34.

Rhee EJ, Yun EJ, Oh KW, Park SE, Park CY, Lee WY, Park SW, Kim SW, Baek KH, Kang MI (2010) The relationship between receptor activator of nuclear factor-kappaB ligand (RANKL) gene polymorphism and aortic calcification in Korean women. Endocr J 57(6):541–549CrossRefPubMed

35.

Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29:155–192CrossRefPubMedCentralPubMed

36.

Hawa G, Brinskelle-Schmal N, Glatz K, Maitzen S, Woloszczuk W (2003) Immunoassay for soluble RANKL (receptor activator of NF-B ligand) in serum. Clin Lab 49:461–463PubMed

37.

Ueland T, Bollerslev J, Wilson SG, Dick IM, Islam FM, Mullin BH et al (2007) No associations between OPG gene polymorphisms or serum levels and measures of osteoporosis in elderly Australian women. Bone 40:175–181CrossRefPubMed

38.

Jørgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen JB (2004) Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Metab 22:132–138CrossRefPubMed

Title: RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus
Authors: A. C. Bonfá
L. P. C. Seguro
V. Caparbo
E. Bonfá
R. M. R. Pereira
Publication date: 01-05-2015
Publisher: Springer London
Published in: Osteoporosis International / Issue 5/2015
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-015-3029-x

At a glance: The STEP trials

Springer Medicine

RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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