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Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene–environment interaction analysis in UK Biobank cohort

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Abstract

Introduction

Serum urate is associated with BMD and may be a protective factor. However, the exact association and mechanism are still unclear. We performed a genome-wide gene–environmental interaction study (GWGEIS) to explore the interaction effects between gene and urate on BMD, using data from the UK Biobank cohort.

Methods

A total of 4575 participants for femur total BMD, 4561 participants for L1–L4 BMD, and 237799 participants for heel BMD were included in the present study. Linear regression models were used to test for associations between urate and BMD (femur total BMD, L1–L4 BMD, heel BMD) by R software. GWGEIS was conducted by PLINK 2.0 using a generalize linear model, adjusted for age, sex, weight, smoking behavior, drinking behavior, physical activity and 10 principle components for population structure.

Results

Results showed that urate was positively associated with femur total BMD, L1–L4 BMD and heel BMD and similar findings were observed in both the male and female subgroups. GWGEIS identified 261 genome-wide significant (P < 5.00 × 10−8) SNP × urate interaction effects for femur total BMD (rs8192585 in NOTCH4, rs116080577 in PBX1, rs9409991 in COL5A1), 17 genome-wide significant SNP × urate interaction effects for heel BMD (rs145344540 in PDE11A and rs78485379 in DKK2), 17 suggestive genome-wide SNP × urate interaction effects (P < 1.00 × 10−5) for L1–L4 BMD (rs10977015 in PTPRD). We also detected genome-wide significant and suggestive SNP × urate interaction effects for BMD in both the male and female subgroups.

Conclusions

This study reported several novel candidate genes, and strengthen the evidence of the interactive effects between gene and urate on the variations of BMD.

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References

  1. Kanis J.A., Melton III L.J., Christiansen C., Johnston C.C., Khaltaev N.J.J.O.B., research m, The diagnosis of osteoporosis. 9 (8), 1137–1141 (1994)

  2. N.C. Wright, K.G. Saag, B. Dawson-Hughes, S. Khosla, E.S. Siris, The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA. Osteoporos. Int. 28(4), 1225–1232 (2017). https://doi.org/10.1007/s00198-016-3865-3

    Article  PubMed  CAS  Google Scholar 

  3. O. Johnell, J.A. Kanis, A. Oden, H. Johansson, C. De Laet, P. Delmas, J.A. Eisman, S. Fujiwara, H. Kroger, D. Mellstrom, P.J. Meunier, L.J. Melton, T. O'Neill, H. Pols, J. Reeve, A. Silman, A. Tenenhouse, Predictive value of BMD for hip and other fractures. J. Bone Min. Res. 20(7), 1185–1194 (2005)

    Article  Google Scholar 

  4. M.A. Christou, G. Ntritsos, G. Markozannes, F. Koskeridis, S.N. Nikas, D. Karasik, D.P. Kiel, E. Evangelou, E.E. Ntzani, A genome-wide scan for pleiotropy between bone mineral density and nonbone phenotypes. Bone Res. 8, 26 (2020). https://doi.org/10.1038/s41413-020-0101-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. H.-F. Zheng, V. Forgetta, Y.-H. Hsu, K. Estrada, A. Rosello-Diez, P.J. Leo, C.L. Dahia, K.H. Park-Min, J.H. Tobias, C. Kooperberg, A. Kleinman, U. Styrkarsdottir, C.-T. Liu, C. Uggla, D.S. Evans, C.M. Nielson, K. Walter, U. Pettersson-Kymmer, S. McCarthy, J. Eriksson, T. Kwan, M. Jhamai, K. Trajanoska, Y. Memari, J. Min, J. Huang, P. Danecek, B. Wilmot, R. Li, W.-C. Chou, L.E. Mokry, A. Moayyeri, M. Claussnitzer, C.-H. Cheng, W. Cheung, C. Medina-Gómez, B. Ge, S.-H. Chen, K. Choi, L. Oei, J. Fraser, R. Kraaij, M.A. Hibbs, C.L. Gregson, D. Paquette, A. Hofman, C. Wibom, G.J. Tranah, M. Marshall, B.B. Gardiner, K. Cremin, P. Auer, L. Hsu, S. Ring, J.Y. Tung, G. Thorleifsson, A.W. Enneman, N.M. van Schoor, de Groot LCPGM, N. van der Velde, B. Melin, J.P. Kemp, C. Christiansen, A. Sayers, Y. Zhou, S. Calderari, J. van Rooij, C. Carlson, U. Peters, S. Berlivet, J. Dostie, A.G. Uitterlinden, S.R. Williams, C. Farber, D. Grinberg, A.Z. LaCroix, J. Haessler, D.I. Chasman, F. Giulianini, L.M. Rose, P.M. Ridker, J.A. Eisman, T.V. Nguyen, J.R. Center, X. Nogues, N. Garcia-Giralt, L.L. Launer, V. Gudnason, D. Mellström, L. Vandenput, N. Amin, C.M. van Duijn, M.K. Karlsson, Ö. Ljunggren, O. Svensson, G. Hallmans, F. Rousseau, S. Giroux, J. Bussière, P.P. Arp, F. Koromani, R.L. Prince, J.R. Lewis, B.L. Langdahl, A.P. Hermann, J.-E.B. Jensen, S. Kaptoge, K.-T. Khaw, J. Reeve, M.M. Formosa, A. Xuereb-Anastasi, K. Åkesson, F.E. McGuigan, G. Garg, J.M. Olmos, M.T. Zarrabeitia, J.A. Riancho, S.H. Ralston, N. Alonso, X. Jiang, D. Goltzman, T. Pastinen, E. Grundberg, D. Gauguier, E.S. Orwoll, D. Karasik, G. Davey-Smith, A.V. Smith, K. Siggeirsdottir, T.B. Harris, M.C. Zillikens, J.B.J. van Meurs, U. Thorsteinsdottir, M.T. Maurano, N.J. Timpson, N. Soranzo, R. Durbin, S.G. Wilson, E.E. Ntzani, M.A. Brown, K. Stefansson, D.A. Hinds, T. Spector, L.A. Cupples, C. Ohlsson, C.M.T. Greenwood, R.D. Jackson, D.W. Rowe, C.A. Loomis, D.M. Evans, C.L. Ackert-Bicknell, A.L. Joyner, E.L. Duncan, D.P. Kiel, F. Rivadeneira, J.B. Richards, Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526(7571), 112–117 (2015). https://doi.org/10.1038/nature14878

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Brustad N., Garland J., Thorsen J., Sevelsted A., Krakauer M., Vinding R.K., Stokholm J., Bønnelykke K., Bisgaard H., Chawes B.L. Effect of High-Dose vs Standard-Dose Vitamin D Supplementation in Pregnancy on Bone Mineralization in Offspring Until Age 6 Years: A Prespecified Secondary Analysis of a Double-Blinded, Randomized Clinical Trial. JAMA Pediatr. (2020). https://doi.org/10.1001/jamapediatrics.2019.6083

  7. S. Cheng, X. Qi, M. Ma, L. Zhang, B. Cheng, C. Liang, L. Liu, P. Li, O.P. Kafle, Y. Wen, F. Zhang, Assessing the relationship between gut microbiota and bone mineral density. Front. Genet. 11, 6 (2020). https://doi.org/10.3389/fgene.2020.00006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. D.-D. Yan, J. Wang, X.-H. Hou, Y.-Q. Bao, Z.-L. Zhang, C. Hu, W.-P. Jia, Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population. Acta Pharm. Sin. 39(4), 626–632 (2018). https://doi.org/10.1038/aps.2017.165

    Article  CAS  Google Scholar 

  9. J. Xiao, W. Chen, X. Feng, W. Liu, Z. Zhang, L. He, Z. Ye, Serum uric acid is associated with lumbar spine bone mineral density in healthy Chinese males older than 50 years. Clin. Inter. Aging 12, 445–452 (2017). https://doi.org/10.2147/CIA.S130690

    Article  CAS  Google Scholar 

  10. J.-H. Lai, S.-F. Luo, L.-F. Hung, C.-Y. Huang, S.-B. Lien, L.-C. Lin, F.-C. Liu, B.L. Yen, L.-J. Ho, Physiological concentrations of soluble uric acid are chondroprotective and anti-inflammatory. Sci. Rep. 7(1), 2359 (2017). https://doi.org/10.1038/s41598-017-02640-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. P.R. Rosenbaum, Discussing hidden bias in observational studies. Ann. Intern. Med. 115(11), 901–905 (1991). https://doi.org/10.7326/0003-4819-115-11-901

    Article  PubMed  CAS  Google Scholar 

  12. S.B. Manuck, J.M. McCaffery, Gene-environment interaction. Annu Rev. Psychol. 65, 41–70 (2014). https://doi.org/10.1146/annurev-psych-010213-115100

    Article  PubMed  Google Scholar 

  13. R. Karlsson Linnér, P. Biroli, E. Kong, S.F.W. Meddens, R. Wedow, M.A. Fontana, M. Lebreton, S.P. Tino, A. Abdellaoui, A.R. Hammerschlag, M.G. Nivard, A. Okbay, C.A. Rietveld, P.N. Timshel, M. Trzaskowski, R.D. Vlaming, C.L. Zünd, Y. Bao, L. Buzdugan, A.H. Caplin, C.-Y. Chen, P. Eibich, P. Fontanillas, J.R. Gonzalez, P.K. Joshi, V. Karhunen, A. Kleinman, R.Z. Levin, C.M. Lill, G.A. Meddens, G. Muntané, S. Sanchez-Roige, F.J.V. Rooij, E. Taskesen, Y. Wu, F. Zhang, A. Auton, J.D. Boardman, D.W. Clark, A. Conlin, C.C. Dolan, U. Fischbacher, P.J.F. Groenen, K.M. Harris, G. Hasler, A. Hofman, M.A. Ikram, S. Jain, R. Karlsson, R.C. Kessler, M. Kooyman, J. MacKillop, M. Männikkö, C. Morcillo-Suarez, M.B. McQueen, K.M. Schmidt, M.C. Smart, M. Sutter, A.R. Thurik, A.G. Uitterlinden, J. White, H.D. Wit, J. Yang, L. Bertram, D.I. Boomsma, T. Esko, E. Fehr, D.A. Hinds, M. Johannesson, M. Kumari, D. Laibson, P.K.E. Magnusson, M.N. Meyer, A. Navarro, A.A. Palmer, T.H. Pers, D. Posthuma, D. Schunk, M.B. Stein, R. Svento, H. Tiemeier, P.R.H.J. Timmers, P. Turley, R.J. Ursano, G.G. Wagner, J.F. Wilson, J. Gratten, J.J. Lee, D. Cesarini, D.J. Benjamin, P.D. Koellinger, J.P. Beauchamp, Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat. Genet. 51(2), 245–257 (2019). https://doi.org/10.1038/s41588-018-0309-3

    Article  PubMed  CAS  Google Scholar 

  14. IPAQ Research Committee. Guidelines for data processing and analysis of the International Physical Activity Questionnaire (IPAQ)-short and long forms. (2005). http://www.ipaq.ki.se/scoring.pdf

  15. C. Bycroft, C. Freeman, D. Petkova, G. Band, L.T. Elliott, K. Sharp, A. Motyer, D. Vukcevic, O. Delaneau, J. O'Connell, A. Cortes, S. Welsh, A. Young, M. Effingham, G. McVean, S. Leslie, N. Allen, P. Donnelly, J. Marchini, The UK Biobank resource with deep phenotyping and genomic data. Nature 562(7726), 203–209 (2018). https://doi.org/10.1038/s41586-018-0579-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. S. Purcell, B. Neale, K. Todd-Brown, L. Thomas, M.A.R. Ferreira, D. Bender, J. Maller, P. Sklar, P.I.W. de Bakker, M.J. Daly, P.C. Sham, PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81(3), 559–575 (2007)

    Article  CAS  Google Scholar 

  17. A. Manichaikul, J.C. Mychaleckyj, S.S. Rich, K. Daly, M. Sale, W.-M. Chen, Robust relationship inference in genome-wide association studies. Bioinformatics 26(22), 2867–2873 (2010). https://doi.org/10.1093/bioinformatics/btq559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. C.C. Chang, C.C. Chow, L.C. Tellier, S. Vattikuti, S.M. Purcell, J.J. Lee, Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015). https://doi.org/10.1186/s13742-015-0047-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. N. Veronese, S. Carraro, G. Bano, C. Trevisan, M. Solmi, C. Luchini, E. Manzato, R. Caccialanza, G. Sergi, D. Nicetto, E. Cereda, Hyperuricemia protects against low bone mineral density, osteoporosis and fractures: a systematic review and meta-analysis. Eur. J. Clin. Invest. 46(11), 920–930 (2016). https://doi.org/10.1111/eci.12677

    Article  PubMed  CAS  Google Scholar 

  20. M. Almeida, L. Han, M. Martin-Millan, C.A. O'Brien, S.C. Manolagas, Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J. Biol. Chem. 282(37), 27298–27305 (2007)

    Article  CAS  Google Scholar 

  21. S. Artavanis-Tsakonas, M.D. Rand, R.J. Lake, Notch signaling: cell fate control and signal integration in development. Science 284(5415), 770–776 (1999)

    Article  CAS  Google Scholar 

  22. J. Yu, E. Canalis, Notch and the regulation of osteoclast differentiation and function. Bone 138, 115474 (2020). https://doi.org/10.1016/j.bone.2020.115474

    Article  PubMed  CAS  Google Scholar 

  23. Y. Shang, S. Smith, X. Hu, Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell 7(3), 159–174 (2016). https://doi.org/10.1007/s13238-016-0250-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. A.W.C. Kung, S.-M. Xiao, S. Cherny, G.H.Y. Li, Y. Gao, G. Tso, K.S. Lau, K.D.K. Luk, Liu J-m, B. Cui, M.-J. Zhang, Z.-L. Zhang, J.-W. He, H. Yue, W.-B. Xia, L.-M. Luo, S.-L. He, D.P. Kiel, D. Karasik, Y.-H. Hsu, L.A. Cupples, S. Demissie, U. Styrkarsdottir, B.V. Halldorsson, G. Sigurdsson, U. Thorsteinsdottir, K. Stefansson, J.B. Richards, G. Zhai, N. Soranzo, A. Valdes, T.D. Spector, P.C. Sham, Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am. J. Hum. Genet. 86(2), 229–239 (2010). https://doi.org/10.1016/j.ajhg.2009.12.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. A.J. Hayes, G.P. Dowthwaite, S.V. Webster, C.W. Archer, The distribution of Notch receptors and their ligands during articular cartilage development. J. Anat. 202(6), 495–502 (2003)

    Article  CAS  Google Scholar 

  26. L. Selleri, M.J. Depew, Y. Jacobs, S.K. Chanda, K.Y. Tsang, K.S. Cheah, J.L. Rubenstein, S. O'Gorman, M.L. Cleary, Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development 128(18), 3543–3557 (2001)

    Article  CAS  Google Scholar 

  27. C.-L. Cheung, B.Y.Y. Chan, V. Chan, S. Ikegawa, I. Kou, H. Ngai, D. Smith, K.D.K. Luk, Q.-Y. Huang, S. Mori, P.-C. Sham, A.W.C. Kung, Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation. Hum. Mol. Genet. 18(4), 679–687 (2009). https://doi.org/10.1093/hmg/ddn397

    Article  PubMed  CAS  Google Scholar 

  28. T. Komori, H. Yagi, S. Nomura, A. Yamaguchi, K. Sasaki, K. Deguchi, Y. Shimizu, R.T. Bronson, Y.H. Gao, M. Inada, M. Sato, R. Okamoto, Y. Kitamura, S. Yoshiki, T. Kishimoto, Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89(5), 755–764 (1997)

    Article  CAS  Google Scholar 

  29. M. Roulet, F. Ruggiero, G. Karsenty, D. LeGuellec, A comprehensive study of the spatial and temporal expression of the col5a1 gene in mouse embryos: a clue for understanding collagen V function in developing connective tissues. Cell Tissue Res. 327(2), 323–332 (2007)

    Article  CAS  Google Scholar 

  30. Y. Fang, P. Wang, L. Xia, S. Bai, Y. Shen, Q. Li, Y. Wang, J. Zhu, J. Du, B. Shen, Aberrantly hydroxymethylated differentially expressed genes and the associated protein pathways in osteoarthritis. PeerJ 7, e6425 (2019). https://doi.org/10.7717/peerj.6425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. D.F.G. Remst, A.B. Blom, E.L. Vitters, R.A. Bank, W.B. van den Berg, E.N. Blaney Davidson, P.M. van der Kraan, Gene expression analysis of murine and human osteoarthritis synovium reveals elevation of transforming growth factor β-responsive genes in osteoarthritis-related fibrosis. Arthritis Rheumatol. (Hoboken, NJ) 66(3), 647–656 (2014). https://doi.org/10.1002/art.38266

    Article  CAS  Google Scholar 

  32. Y.-F. Wu, N. Matsuo, H. Sumiyoshi, H. Yoshioka, Sp7/Osterix is involved in the up-regulation of the mouse pro-α1(V) collagen gene (Col5a1) in osteoblastic cells. Matrix Biol. 29(8), 701–706 (2010). https://doi.org/10.1016/j.matbio.2010.09.002

    Article  PubMed  CAS  Google Scholar 

  33. X. Zhang, G. Zhao, Y. Zhang, J. Wang, Y. Wang, L. Cheng, M. Sun, Y. Rui, Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis. Biochem. Biophys. Res. Commun. 504(4), 771–776 (2018). https://doi.org/10.1016/j.bbrc.2018.08.094

    Article  PubMed  CAS  Google Scholar 

  34. U. Styrkarsdottir, O.A. Stefansson, K. Gunnarsdottir, G. Thorleifsson, S.H. Lund, L. Stefansdottir, K. Juliusson, A.B. Agustsdottir, F. Zink, G.H. Halldorsson, E.V. Ivarsdottir, S. Benonisdottir, H. Jonsson, A. Gylfason, K. Norland, K. Trajanoska, C.G. Boer, L. Southam, J.C.S. Leung, N.L.S. Tang, T.C.Y. Kwok, J.S.W. Lee, S.C. Ho, I. Byrjalsen, J.R. Center, S.H. Lee, J.-M. Koh, L.S. Lohmander, L.T. Ho-Pham, T.V. Nguyen, J.A. Eisman, J. Woo, P.-C. Leung, J. Loughlin, E. Zeggini, C. Christiansen, F. Rivadeneira, J. van Meurs, A.G. Uitterlinden, B. Mogensen, H. Jonsson, T. Ingvarsson, G. Sigurdsson, R. Benediktsson, P. Sulem, I. Jonsdottir, G. Masson, H. Holm, G.L. Norddahl, U. Thorsteinsdottir, D.F. Gudbjartsson, K. Stefansson, Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures. Nat. Commun. 10(1), 2358 (2019). https://doi.org/10.1038/s41467-019-10425-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. A.W. James, J. Shen, X. Zhang, G. Asatrian, R. Goyal, J.H. Kwak, L. Jiang, B. Bengs, C.T. Culiat, A.S. Turner, H.B. Seim Iii, B.M. Wu, K. Lyons, J.S. Adams, K. Ting, C. Soo, NELL-1 in the treatment of osteoporotic bone loss. Nat. Commun. 6, 7362 (2015). https://doi.org/10.1038/ncomms8362

    Article  PubMed  CAS  Google Scholar 

  36. J.-K. Park, E.-M. Lee, A.-Y. Kim, E.-J. Lee, C.-W. Min, K.-K. Kang, M.-M. Lee, K.-S. Jeong, Vitamin C deficiency accelerates bone loss inducing an increase in PPAR-γ expression in SMP30 knockout mice. Int J. Exp. Pathol. 93(5), 332–340 (2012). https://doi.org/10.1111/j.1365-2613.2012.00820.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. X. Li, P. Liu, W. Liu, P. Maye, J. Zhang, Y. Zhang, M. Hurley, C. Guo, A. Boskey, L. Sun, S.E. Harris, D.W. Rowe, H.Z. Ke, D. Wu, Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat. Genet 37(9), 945–952 (2005)

    Article  CAS  Google Scholar 

  38. L. Chen, K. Wang, Y. Shao, J. Huang, X. Li, J. Shan, D. Wu, J.J. Zheng, Structural insight into the mechanisms of Wnt signaling antagonism by Dkk. J. Biol. Chem. 283(34), 23364–23370 (2008). https://doi.org/10.1074/jbc.M802375200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. R. Baron, M. Kneissel, WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19(2), 179–192 (2013). https://doi.org/10.1038/nm.3074

    Article  PubMed  CAS  Google Scholar 

  40. Y. Mikami, D. Omagari, Y. Mizutani, M. Hayatsu, T. Ushiki, H. Tsuda, Dual effect of polyphosphate on mineralization of rat osteoblast ROS17/2.8 cells in a dose-dependent manner. J. Pharm. Sci. 138(3), 209–213 (2018). https://doi.org/10.1016/j.jphs.2018.10.002

    Article  CAS  Google Scholar 

  41. T. Kajander, J. Kellosalo, A. Goldman, Inorganic pyrophosphatases: one substrate, three mechanisms. FEBS Lett. 587(13), 1863–1869 (2013). https://doi.org/10.1016/j.febslet.2013.05.003

    Article  PubMed  CAS  Google Scholar 

  42. S.H. Soderling, J.A. Beavo, Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr. Opin. Cell Biol. 12(2), 174–179 (2000)

    Article  CAS  Google Scholar 

  43. W. Shi, Y. Gao, Y. Wang, J. Zhou, Z. Wei, X. Ma, H. Ma, C.J. Xian, J. Wang, K. Chen, The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts. J. Biol. Chem. 292(51), 20883–20896 (2017). https://doi.org/10.1074/jbc.M117.809517

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. V. Vives, M. Laurin, G. Cres, P. Larrousse, Z. Morichaud, D. Noel, J.-F. Côté, A. Blangy, The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts. J. Bone Min. Res. 26(5), 1099–1110 (2011). https://doi.org/10.1002/jbmr.282

    Article  CAS  Google Scholar 

  45. P. Jurdic, F. Saltel, A. Chabadel, O. Destaing, Podosome and sealing zone: specificity of the osteoclast model. Eur. J. Cell Biol. 85(3-4), 195–202 (2006)

    Article  CAS  Google Scholar 

  46. K. Tsuritani, J. Takeda, J. Sakagami, A. Ishii, T. Eriksson, T. Hara, H. Ishibashi, Y. Koshihara, K. Yamada, Y. Yoneda, Cytokine receptor-like factor 1 is highly expressed in damaged human knee osteoarthritic cartilage and involved in osteoarthritis downstream of TGF-beta. Calcif. Tissue Int. 86(1), 47–57 (2010). https://doi.org/10.1007/s00223-009-9311-1

    Article  PubMed  CAS  Google Scholar 

  47. Z. Zhou, X. Sheng, Z. Zhang, K. Zhao, L. Zhu, G. Guo, S.G. Friedenberg, L.S. Hunter, W.S. Vandenberg-Foels, W.E. Hornbuckle, U. Krotscheck, E. Corey, N.S. Moise, N.L. Dykes, J. Li, S. Xu, L. Du, Y. Wang, J. Sandler, G.M. Acland, G. Lust, R.J. Todhunter, Differential genetic regulation of canine hip dysplasia and osteoarthritis. PLoS ONE 5(10), e13219 (2010). https://doi.org/10.1371/journal.pone.0013219

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. M. Freidin, M. Kraatari, S. Skarp, J. Määttä, J. Kettunen, J. Niinimäki, J. Karppinen, F. Williams, M. Männikkö, Genome-wide meta-analysis identifies genetic locus on chromosome 9 associated with Modic changes. J. Med. Genet. 56(7), 420–426 (2019). https://doi.org/10.1136/jmedgenet-2018-105726

    Article  PubMed  CAS  Google Scholar 

  49. Y. Pu, H. Zhao, X. Wu, M. Mei, B. Shen, The long noncoding RNA Ptprd-IR is a novel molecular target for TGF-β1-mediated nephritis. Int. J. Biochem. Cell Biol. 122, 105742 (2020). https://doi.org/10.1016/j.biocel.2020.105742

    Article  PubMed  CAS  Google Scholar 

  50. W.R. Thompson, A.S. Majid, K.J. Czymmek, A.L. Ruff, J. García, R.L. Duncan, M.C. Farach-Carson, Association of the α(2)δ(1) subunit with Ca(v)3.2 enhances membrane expression and regulates mechanically induced ATP release in MLO-Y4 osteocytes. J. Bone Min. Res. 26(9), 2125–2139 (2011). https://doi.org/10.1002/jbmr.437

    Article  CAS  Google Scholar 

  51. N. Amiri, J.K. Christians, PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice. Growth Horm. IGF Res. 25(6), 274–280 (2015). https://doi.org/10.1016/j.ghir.2015.09.003

    Article  PubMed  CAS  Google Scholar 

  52. K.E. Govoni, D.J. Baylink, S. Mohan, The multi-functional role of insulin-like growth factor binding proteins in bone. Pediatr. Nephrol. 20(3), 261–268 (2005)

    Article  Google Scholar 

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Acknowledgements

This study is supported by the National Natural Scientific Foundation of China (81922059, 81972980, 81703177).

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  1. These authors contributed equally: Yao Yao, Xiaomeng Chu

Authors and Affiliations

  1. Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, China

    Yao Yao, Xiaomeng Chu, Mei Ma, Jing Ye, Yan Wen, Ping Li, Bolun Cheng, Shiqiang Cheng, Lu Zhang, Li Liu, Xin Qi, Chujun Liang, Om Prakash Kafle, Cuiyan Wu, Sen Wang, Xi Wang, Yujie Ning & Feng Zhang

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  1. Yao Yao
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Correspondence to Feng Zhang.

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Yao, Y., Chu, X., Ma, M. et al. Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene–environment interaction analysis in UK Biobank cohort. Endocrine 73, 702–711 (2021). https://doi.org/10.1007/s12020-021-02760-8

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