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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Comparison of Cytokine Profile between Postmenopausal Women with and Without Osteoporosis – A Case-Control Study

Author(s): Geok Ting Soh, Affaf Hulma Mohammad, Sharifah Nur Liyana Syed Isa, Kok-Yong Chin* and Norazlina Mohamed*

Volume 23, Issue 6, 2023

Published on: 27 December, 2022

Page: [811 - 817] Pages: 7

DOI: 10.2174/1871530323666221114111029

Price: $65

Abstract

Background: Chronic low-grade inflammation is involved in the pathogenesis of postmenopausal osteoporosis, but the cytokines implicated remain elusive.

Objective: This study aimed to compare the difference in cytokine profile between postmenopausal women with and without osteoporosis in Klang Valley, Malaysia.

Methods: Postmenopausal women with (n = 20) and without osteoporosis (n = 20) were recruited for this study. Their bone health status was determined using dual-energy X-ray absorptiometry. Their fasting blood was collected for proteomic analysis. A protein array was performed for four subjects randomly selected from each group to screen the potential cytokines. Three cytokines at least 20% different between groups and consistently expressed by each subject were selected for validation using enzyme-linked immunosorbent assays (ELISA).

Results: The protein array screening demonstrated that platelet-derived growth factor-BB, interleukin- 6 receptor (IL-6R), and tissue inhibitor of metallopeptidase-2 were higher in women with osteoporosis than women without osteoporosis (n = 4 per group), and consistently expressed by all women. Only body mass index (BMI)-adjusted logarithmically transformed IL-6R levels were lower among postmenopausal women with osteoporosis compared to women with normal bone health (p = 0.026) (n = 16 per group) in the ELISA test.

Conclusion: IL-6R was lower among postmenopausal women with osteoporosis compared to women with normal bone health after adjusting for BMI. However, a large-scale epidemiological study with proteomic analysis needs to confirm the findings.

Keywords: Osteopororsis, inflammation, interleukin-6 receptor, platelet-derived growth factor-BB, tissue inhibitor of metallopeptidase- 2, enzyme-linked immunosorbent assays.

Graphical Abstract
[1]
Pouresmaeili F, Kamali Dehghan B, Kamarehei M, Yong MG. A comprehensive overview on osteoporosis and its risk factors. Ther Clin Risk Manag 2018; 14: 2029-49.
[http://dx.doi.org/10.2147/TCRM.S138000] [PMID: 30464484]
[2]
Shevroja E, Cafarelli FP, Guglielmi G, Hans D. DXA parameters, trabecular bone score (TBS) and bone mineral density (BMD), in fracture risk prediction in endocrine-mediated secondary osteoporosis. Endocrine 2021; 74(1): 20-8.
[http://dx.doi.org/10.1007/s12020-021-02806-x] [PMID: 34245432]
[3]
Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a World Health Organization Study Group. Geneva: World Health Organization 1994. Available from: https://apps.who.int/iris/handle/10665/39142
[4]
Subramaniam S, Chan CY, Soelaiman IN, et al. The performance of osteoporosis self-assessment tool for Asians (OSTA) in identifying the risk of osteoporosis among Malaysian population aged 40 years and above. Arch Osteoporos 2019; 14(1): 117.
[http://dx.doi.org/10.1007/s11657-019-0666-2] [PMID: 31781876]
[5]
Carlson BC, Robinson WA, Wanderman NR, et al. A review and clinical perspective of the impact of osteoporosis on the spine. Geriatr Orthop Surg Rehabil 2019; 10: 1-8.
[http://dx.doi.org/10.1177/2151459319861591] [PMID: 31360592]
[6]
Zhuang H, Wang P, Li Y, Lin J, Yao X, Xu H. Analysis of related factors of brittle hip fracture in postmenopausal women with osteoporosis. Orthop Surg 2020; 12(1): 194-8.
[http://dx.doi.org/10.1111/os.12605] [PMID: 31943831]
[7]
Chan CY, Subramaniam S, Mohamed N, et al. Determinants of bone health status in a multi-ethnic population in Klang Valley, Malaysia. Int J Environ Res Public Health 2020; 17(2): 384.
[http://dx.doi.org/10.3390/ijerph17020384] [PMID: 31936034]
[8]
Subramaniam S, Chan CY, Soelaiman IN, et al. Prevalence and predictors of osteoporosis among the Chinese population in Klang Valley, Malaysia. Appl Sci 2019; 9(9): 1820.
[http://dx.doi.org/10.3390/app9091820]
[9]
Drake MT, Khosla S. Sex steroids and the pathogenesis of osteoporosis. New Jersey: in: Primer on the Metabolic Bone Diseases And Disorders Of Mineral Metabolism. John Wiley & Sons, Inc. 2018; pp. 412-8.
[http://dx.doi.org/10.1002/9781119266594.ch52]
[10]
Kenkre JS, Bassett JHD. The bone remodelling cycle. Ann Clin Biochem 2018; 55(3): 308-27.
[http://dx.doi.org/10.1177/0004563218759371] [PMID: 29368538]
[11]
Khosla S, Pacifici R. Estrogen deficiency and the pathogenesis of osteoporosis. In: Dempster DW, Cauley JA, Bouxsein ML, Cosman F, Eds. Marcus and Feldman’s Osteoporosis. (5th ed.). Cambridge: Academic Press 2021; pp. 773-97.
[http://dx.doi.org/10.1016/B978-0-12-813073-5.00032-0]
[12]
Mohamad NV, Ima-Nirwana S, Chin KY. Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? a review of current evidence. Endocr Metab Immune Disord Drug Targets 2020; 20(9): 1478-87.
[http://dx.doi.org/10.2174/1871530320666200604160614] [PMID: 32496996]
[13]
Azizieh F, Raghupathy R, Shehab D, Al-Jarallah K, Gupta R. Cytokine profiles in osteoporosis suggest a proresorptive bias. Menopause 2017; 24(9): 1057-64.
[http://dx.doi.org/10.1097/GME.0000000000000885] [PMID: 28609384]
[14]
Al-Daghri NM, Aziz I, Yakout S, et al. Inflammation as a contributing factor among postmenopausal Saudi women with osteoporosis. Medicine 2017; 96(4): e5780.
[http://dx.doi.org/10.1097/MD.0000000000005780] [PMID: 28121926]
[15]
Subramaniam S, Chan CY, Soelaiman IN, et al. Development of osteoporosis screening algorithm for population aged 50 years and above in Klang Valley, Malaysia. Int J Environ Res Public Health 2020; 17(7): 2526.
[http://dx.doi.org/10.3390/ijerph17072526] [PMID: 32272697]
[16]
Chan CY, Subramaniam S, Chin KY, et al. Levels of knowledge, beliefs, and practices regarding osteoporosis and the associations with bone mineral density among populations more than 40 years old in Malaysia. Int J Environ Res Public Health 2019; 16(21): 4115.
[http://dx.doi.org/10.3390/ijerph16214115] [PMID: 31731507]
[17]
Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause - global prevalence, physiology and implications. Nat Rev Endocrinol 2018; 14(4): 199-215.
[http://dx.doi.org/10.1038/nrendo.2017.180] [PMID: 29393299]
[18]
Pelekanou V, Kampa M, Kiagiadaki F, et al. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1. J Leukoc Biol 2016; 99(2): 333-47.
[http://dx.doi.org/10.1189/jlb.3A0914-430RR] [PMID: 26394816]
[19]
Villa A, Rizzi N, Vegeto E, Ciana P, Maggi A. Estrogen accelerates the resolution of inflammation in macrophagic cells. Sci Rep 2015; 5(1): 15224.
[http://dx.doi.org/10.1038/srep15224] [PMID: 26477569]
[20]
Fischer V, Kalbitz M, Müller-Graf F, et al. Influence of menopause on inflammatory cytokines during murine and human bone fracture healing. Int J Mol Sci 2018; 19(7): 2070.
[http://dx.doi.org/10.3390/ijms19072070] [PMID: 30013010]
[21]
Wang Q, Ferreira DLS, Nelson SM, Sattar N, Ala-Korpela M, Lawlor DA. Metabolic characterization of menopause: Cross-sectional and longitudinal evidence. BMC Med 2018; 16(1): 17.
[http://dx.doi.org/10.1186/s12916-018-1008-8] [PMID: 29402284]
[22]
Wu D, Cline-Smith A, Shashkova E, Perla A, Katyal A, Aurora R. T-cell mediated inflammation in postmenopausal osteoporosis. Front Immunol 2021; 12: 687551.
[http://dx.doi.org/10.3389/fimmu.2021.687551] [PMID: 34276675]
[23]
Fang H, Zhang H, Wang Z, Zhou Z, Li Y, Lu L. Systemic immune‐inflammation index acts as a novel diagnostic biomarker for postmenopausal osteoporosis and could predict the risk of osteoporotic fracture. J Clin Lab Anal 2020; 34(1): e23016.
[http://dx.doi.org/10.1002/jcla.23016] [PMID: 31423643]
[24]
Liu Q, Zhou Y, Li Z. PDGF-BB promotes the differentiation and proliferation of MC3T3-E1 cells through the Src/JAK2 signaling pathway. Mol Med Rep 2018; 18(4): 3719-26.
[http://dx.doi.org/10.3892/mmr.2018.9351] [PMID: 30106097]
[25]
Xie H, Cui Z, Wang L, et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 2014; 20(11): 1270-8.
[http://dx.doi.org/10.1038/nm.3668] [PMID: 25282358]
[26]
Hock JM, Canalis E. Platelet-derived growth factor enhances bone cell replication, but not differentiated function of osteoblasts. Endocrinology 1994; 134(3): 1423-8.
[http://dx.doi.org/10.1210/endo.134.3.8119182] [PMID: 8119182]
[27]
Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE. Recombinant human platelet-derived growth factor: biology and clinical applications. J Bone Joint Surg Am 2008; 90(S1): 48-54.
[http://dx.doi.org/10.2106/JBJS.G.01231] [PMID: 18292357]
[28]
Tang L, Xia Z, Luo Z, Long H, Zhu Y, Zhao S. Low plasma PDGF-BB levels are associated with estradiol in postmenopausal osteoporosis. J Int Med Res 2017; 45(4): 1332-9.
[http://dx.doi.org/10.1177/0300060517706630] [PMID: 28606019]
[29]
Campana L, Iredale J. matrix metalloproteinases and their inhibitors. In: Gandhi CR, Pinzani M, Eds. Stellate Cells in Health and Disease. Boston: Academic Press 2015; pp. 107-24.
[http://dx.doi.org/10.1016/B978-0-12-800134-9.00007-5]
[30]
Azevedo A, Prado AF, Feldman S, de Figueiredo FAT, dos Santos MCG, Issa JPM. MMPs are involved in osteoporosis and are correlated with cardiovascular diseases. Curr Pharm Des 2018; 24(16): 1801-10.
[http://dx.doi.org/10.2174/1381612824666180604112925] [PMID: 29865998]
[31]
Valacca C, Tassone E, Mignatti P. TIMP-2 interaction with MT1-MMP activates the AKT pathway and protects tumor cells from apoptosis. PLoS One 2015; 10(9): e0136797.
[http://dx.doi.org/10.1371/journal.pone.0136797] [PMID: 26331622]
[32]
Lafleur MA, Handsley MM, Edwards DR. Metalloproteinases and their inhibitors in angiogenesis. Expert Rev Mol Med 2003; 5(23): 1-39.
[http://dx.doi.org/10.1017/S1462399403006628] [PMID: 14585170]
[33]
Shibutani T, Yamashita K, Aoki T, Iwayama Y, Nishikawa T, Hayakawa T. Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption. J Bone Miner Metab 1999; 17(4): 245-51.
[http://dx.doi.org/10.1007/s007740050091] [PMID: 10575588]
[34]
Sobue T, Hakeda Y, Kobayashi Y, et al. Tissue inhibitor of metalloproteinases 1 and 2 directly stimulate the bone-resorbing activity of isolated mature osteoclasts. J Bone Miner Res 2001; 16(12): 2205-14.
[http://dx.doi.org/10.1359/jbmr.2001.16.12.2205] [PMID: 11760833]
[35]
Kramer FJ, Meyer M, Morgan D, et al. Tissue inhibitor of metalloproteinases II (TIMP-2) is an osteoanabolic factor in vitro and in vivo. Eur J Med Res 2008; 13(6): 292-8.
[PMID: 18558556]
[36]
Feng W, Liu H, Luo T, et al. Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways. Sci Rep 2017; 7(1): 41411.
[http://dx.doi.org/10.1038/srep41411] [PMID: 28128332]
[37]
Zhao R. Immune regulation of osteoclast function in postmenopausal osteoporosis: A critical interdisciplinary perspective. Int J Med Sci 2012; 9(9): 825-32.
[http://dx.doi.org/10.7150/ijms.5180] [PMID: 23136547]
[38]
Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 2012; 8(9): 1237-47.
[http://dx.doi.org/10.7150/ijbs.4989] [PMID: 23136552]
[39]
Rose-John S. The soluble interleukin 6 receptor: Advanced therapeutic options in inflammation. Clin Pharmacol Ther 2017; 102(4): 591-8.
[http://dx.doi.org/10.1002/cpt.782] [PMID: 28675418]
[40]
Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble Interleukin 6 receptor: Generation and role in inflammation and cancer. Eur J Cell Biol 2011; 90(6-7): 484-94.
[http://dx.doi.org/10.1016/j.ejcb.2010.10.007] [PMID: 21145125]
[41]
Tamura T, Udagawa N, Takahashi N, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci 1993; 90(24): 11924-8.
[http://dx.doi.org/10.1073/pnas.90.24.11924] [PMID: 8265649]
[42]
Giuliani N, Sansoni P, Girasole G, et al. Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 2001; 36(3): 547-57.
[http://dx.doi.org/10.1016/S0531-5565(00)00220-5] [PMID: 11250125]
[43]
Abrahamsen B, Bonnevie-Nielsen V, Ebbesen EN, Gram J, Beck-Nielsen H. Cytokines and bone loss in a 5-year longitudinal study--hormone replacement therapy suppresses serum soluble interleukin-6 receptor and increases interleukin-1-receptor antagonist: The danish osteoporosis prevention study. J Bone Miner Res 2000; 15(8): 1545-54.
[http://dx.doi.org/10.1359/jbmr.2000.15.8.1545] [PMID: 10934653]
[44]
Nishimura R, Moriyama K, Yasukawa K, Mundy GR, Yoneda T. Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. J Bone Miner Res 1998; 13(5): 777-85.
[http://dx.doi.org/10.1359/jbmr.1998.13.5.777] [PMID: 9610741]
[45]
d’Elia H, Mattsson LÅ, Ohlsson C, Nordborg E, Carlsten H. Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels of soluble IL-6 receptor and higher insulin-like growth factor 1. Arthritis Res 2003; 5(4): R202-9.
[http://dx.doi.org/10.1186/ar761] [PMID: 12823855]
[46]
Chin KY, Wong SK, Ekeuku SO, Pang KL. Relationship between metabolic syndrome and bone health – an evaluation of epidemiological studies and mechanisms involved. Diabetes Metab Syndr Obes 2020; 13: 3667-90.
[http://dx.doi.org/10.2147/DMSO.S275560] [PMID: 33116718]
[47]
Wong S, Chin KY, Suhaimi F, Ahmad F, Ima-Nirwana S. The relationship between metabolic syndrome and osteoporosis: A review. Nutrients 2016; 8(6): 347.
[http://dx.doi.org/10.3390/nu8060347] [PMID: 27338453]
[48]
Kuo FC, Huang YH, Lin FH, et al. Circulating soluble IL-6 receptor concentration and visceral adipocyte size are related to insulin resistance in taiwanese adults with morbid obesity. Metab Syndr Relat Disord 2017; 15(4): 187-93.
[http://dx.doi.org/10.1089/met.2016.0135] [PMID: 28346858]
[49]
Sindhu S, Thomas R, Shihab P, Sriraman D, Behbehani K, Ahmad R. Obesity is a positive modulator of IL-6R and IL-6 expression in the subcutaneous adipose tissue: Significance for metabolic inflammation. PloS one 2015; 10(7): e0133494.
[50]
Pacifici R. Cytokines, estrogen, and postmenopausal osteoporosis - the second decade. Endocrinology 1998; 139(6): 2659-61.
[http://dx.doi.org/10.1210/endo.139.6.6087] [PMID: 9607769]
[51]
ter Horst R, Jaeger M, Smeekens SP, et al. Host and environmental factors influencing individual human cytokine responses. Cell 2016; 167(4): 1111-1124.e13.
[http://dx.doi.org/10.1016/j.cell.2016.10.018] [PMID: 27814508]

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