[20] Guccione AA et al. 1994

[21] Felson DT, Lawrence RC et al. 2009

[22] Mishra A, Sanghi D, Sharma AC, Raj S, Maurya SS, Avasthi S, Singh A, Parmar D, Srivastava RN. "Association of polymorphism in growth and differentiation factor 5 gene with osteoarthritis knee". American Journal of Biochemistry and Biotechnology. 2013; 9(1):1-7

[23] Singh AK, Kalaivani M, Krishnan A, Aggarwal PK et al. Prevalence of Osteoarthritis of Knee Among Elderly Persons in Urban Slums Using American College of Rheumatology (ACR) criteria. J Clin Diagn Res. 2014 Sep; 8(9): JC09–JC11.

[24] Martin JA et al. 2002

[25] Awasthi S, Mishra A, Sanghi D, Singh A, Parihar R, Pankaj R, Ganesh S, Srivastava RN. "Association of Intronic Single nucleotide polymorphism SNP of CALM 1 gene with Osteoarthritis of the Knee in the Indian population, a case-control study". Internet Journal of Medical Update, 2012;7(1)

[26] Sanghi D, Mishra A, Sharma AC, Natu SM, Srivastava RN, Singh A, Agarwal S. "Does Vitamin D Improve Osteoarthritis of the Knee, A Randomized Controlled Pilot Trial".Clin Orthop Relat Res. 2013; 471(8). DOI 10.1007/s11999-013-3201-6

[27] Amar Chandra Sharma, RajeshwarNath Srivastava, SudeeptiRatan Srivastava, DevendraParmar, Ajai Singh, Saloni Raj. Association between Single Nucleotide Polymorphisms of SMAD3 and BMP5 with the Risk of Knee Osteoarthritis. JCDR/2017/22371.10073

[28] Subramanyam K, Poornima S, Khan I A and Hasan Q. Exploration of Genetic Association Studies with Collagen Variants in Clinically Diagnosed Primary Knee Osteoarthritis in South Indian Population: A Non-replication Study. Journal of Arthritis, 2016, 5:5.

[29] Gonzalez A. Osteoarthritis year 2013 in review: genetics and genomics. Asian Biomedicine Vol. 5 No. 1 February 2011; 23-36

[30] Yau Michelle S et al. Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. Arthritis & Rheumatology. February 2017, Vol. 69, No. 2.

[31] Syddall, CM; Reynard, L.N.; Young, D.A.; Loughlin, J. The identification of trans-acting factors that regulate the expression of GDF5 via the osteoarthritis susceptibility SNP rs143383. PLoS Genet. 2013, 9.

[32] Zhang R, Yao J, Xu P, Ji B, Luck JV, Chin B, et al. A comprehensive meta-analysis of the association between genetic variants of *GDF5* and Osteoarthritis of the knee, hip and hand. Inflammation Research 2015;64(6):405-414

[33] Miyamoto, Y.; Mabuchi, A.; Shi, D. et. al. A functional polymorphism in the 51 UTR of GDF5 is associated with susceptibility to Osteoarthritis. Nat. Genet. 2007, 39, 529-533.

[34] Valdes, A.M.; Spector, T.D.; Tamm, A. et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum. 2010, 62, 2347-2352.

[35] Chapman, K.; Takahashi, A.; Meulenbelt, I. et al. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 51 UTR of GDF5 with osteoarthritis susceptibility. Hum. Mol. Genet. 2008, 17, 1497-1504.

[36] Kizawa, H.; Kou, I.; Iida, A. et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to Osteoarthritis. Nat. Genet. 2005, 37, 138-144.

[37] Valdes, A.M.; Evangelou, E.; Kerkhof, H.J.M. et al. The GDF5 rs143383 polymorphism is associated with Osteoarthritis of the knee with genome-wide statistical significance. Ann. Rheum. Dis. 2011, 70, 873-875.

[38] Attur M, Belitskaya-Levy I, Cheongeun, Krasnokutsky S, Greenberg J, Samuels J, et al. Increased Interleukin-1 Gene Expression in Peripheral Blood Leukocytes Is Associated With Increased Pain and Predicts Risk for Progression of Symptomatic Knee Osteoarthritis. Arthritis & Rheumatism 2011; 63 (7):1908-1917. DOI 10.1002/art.30360

[39] Yerges-Armstrong LM, Yau MS, Liu Y, Krishnan S, Renner JB, Eaton CB, et al. Association Analysis of BMD associated SNPs with Knee Osteoarthritis. Journal of Bone and Mineral Research 2014;29(6):1373-1379. DOI: 10.1002/jbmr.2160

[40] Luo SX, Zhang XH, Zhang JJ, Long GH, Dong GF, Su W, et al. Genetic Polymorphisms of Interleukin-16 and Risk of Knee Osteoarthritis. PLOS ONE | .2015. DOI:10.1371/journal. pone.0123442

[41] Torres F, et al. Polymorphic variation of hypoxia-inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study. BMC Musculoskeletal Disorders 2015; 16:218 DOI 10.1186/ s12891-015-0678-z

[42] Ho KW, Wallace M and Fillingim R. Single-nucleotide polymorphism in COL11A2 associated with thermal hyperalgesia in knee osteoarthritis (P1.210).Neurology 2017;88(16):210

[43] Li H, Zhang X, Cao Y, Hu S, Peng F, Zhou J1 and Li J. Association between

EN1 rs4144782 and susceptibility of knee osteoarthritis: A case-control study. Oncotarget, 2017;8(22): 36650-36657

[44] Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol 1997. 15:675-705.

[45] Berckmans RJ, Nieuwland R, Kraan MC, Schaap MC, Pots D, Smeets TJ, Sturk A, Tak PP: Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes**.** *Arthritis Res Ther* 2005, 7:R536-R544.

[46] Bleasel JF, Holderbaum D, Brancolini V, Moskowitz RW, Considine EL, Prockop DJ, Devoto M, Williams CJ. Five families with arginine 519-cysteine mutation in COL2A1: evidence for three distinct founders. Hum Mutat. 1998; 12(3):172-6.

[47] Chou P, Soong LN, Lin HY. Community-based epidemiological study on hyperuricemia in Pu-Li, Taiwan. J Formos Med Assoc. 1993 Jul; 92(7):597-602.

[48] Corrigall, V. M., Arastu, M., Khan, S., Shah, C., Fife, M., Smeets, T., Tak, P.-P., Panayi, G. S. Functional IL-2 receptor beta (CD122) and gamma (CD132) chains are expressed by fibroblast-like synoviocytes: activation by IL-2 stimulates monocyte chemoattractant protein-1 production. J. Immun. 2001;166: 4141-4147.

[49] Creamer P, Lethbridge-Cejku M, Hochberg MC. Factors associated with functional impairment in symptomatic knee osteoarthritis. Rheumatology (Oxford). 2000 May;39(5):490-6.

[50] Ducy P, Karsenty G. The family of bone morphogenetic proteins. Kidney Int 2000; 57:2207-14.

[51] Edwards CJ, Francis-West PH: Bone morphogenetic proteins in the

**241**

*Genetics in Osteoarthritis Knee*

31:33-42.

Sep 16.

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

frequency of MCP-1 promoter 22518 polymorphism in the Korean population and Korean patients with rheumatoid arthritis, systemic lupus erythematosus and adult-onset Still's disease. Eur J Immunogenet 2002; 29:413-16.

[60] Iikuni N, Okamoto H, Yoshio T, Sato E, Kamitsuji S, Iwamoto T, et al. Raised monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus.

Ann Rheum Dis 2006; 65:253-6.

[61] James M Wilkins\*1, Lorraine Southam1, Zehra Mustafa1, Kay Chapman1 and John Loughlin2 Association of a functional

microsatellite within intron 1 of the

[62] gene with susceptibility to Osteoarthritis. *BMC Medical Genetics*

[63] Jones C. M., Lyons K. M., and Hogan B. L., Involvement of Bone Morphogenetic Protein-4 (BMP-4) and *Vgr-1* in morphogenesis and neurogenesis in the mouse. Development 1991, **111**:531-542

Randle S, Cowie S, du Sart D, McGrath S, Edwards M, Savarirayan R. Premature arthritis is a distinct type II collagen phenotype. Arthritis Rheum. 2010 May;

[64] Kannu P, Bateman JF,

[65] Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis. 1957

[66] King, J. A., P. C. Marker, K. J. Seung, and Kingsley D. M., BMP5 and the molecular, skeletal, and soft-tissue alterations in *short ear* mice. Dev. Biol.

[67] King J. A., Storm E. E., Marker P. C, Dileone R. J., and. Kingsley D. M, The role of BMPs and GDFs in development of region-specific skeletal structures. Ann. NY Acad. Sci. 1996; **785**:70-79

62(5):1421-30.

Dec;16(4):494-502

1994 **166**:112-122

2009, 10:141

[52] Galvez-Rosas A, González-Huerta C, Borgonio-Cuadra VM, Duarte-Salazár C,

[53] Hahn, G. V., Cohen, R. B., Wozney, J. M., Levitz, C. L., Shore, E. M., Zasloff, M. A., Kaplan, F. S. A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7. Genomics; 1992, 14: 759-762.

[54] Hatakeyama Y, Tuan RS, Shum L: Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis. *J Cell Biochem* 2004, 91:1204-1217.

[55] Herbert RD, Gabriel M. Effects of stretching before and after exercising on muscle soreness and risk of injury: a systematic review. BMJ. 2002 Aug 31;

[56] Hogan B. L.; Bone morphogenetic proteins: multifunctional regulators of vertebrate development. *Genes Dev.*

[57] Holderbaum D, Malemud CJ, Moskowitz RW, Haqqi TM. Human cartilage from late-stage familial Osteoarthritis transcribes type II collagen mRNA encoding a cysteine in position 519. Biochem Biophys Res Commun. 1993 May 14; 192(3):1169-74.

[58] Hunter DJ, Felson DT.

332(7542):639-42.

Osteoarthritis. BMJ. 2006 Mar 18;

[59] Hwang SY, Cho ML, Park B, Kim JY, Kim YH, Min DJ, et al. Allelic

325(7362):468.

1996 10: 1580-1594

Lara-Alvarado L, de los Angeles Soria-Bastida M, Cortés-González S, Ramón-Gallegos E, Miranda-Duarte A. A COL2A1 gene polymorphism is related with advanced stages of osteoarthritis of the knee in Mexican Mestizo population. Rheumatol Int. 2010 Jun; 30(8):1035-9. Epub 2009

development and healing of synovial joints. *Semin Arthritis Rheum* 2001,

*Genetics in Osteoarthritis Knee DOI: http://dx.doi.org/10.5772/intechopen.93890*

development and healing of synovial joints. *Semin Arthritis Rheum* 2001, 31:33-42.

[52] Galvez-Rosas A, González-Huerta C, Borgonio-Cuadra VM, Duarte-Salazár C, Lara-Alvarado L, de los Angeles Soria-Bastida M, Cortés-González S, Ramón-Gallegos E, Miranda-Duarte A. A COL2A1 gene polymorphism is related with advanced stages of osteoarthritis of the knee in Mexican Mestizo population. Rheumatol Int. 2010 Jun; 30(8):1035-9. Epub 2009 Sep 16.

[53] Hahn, G. V., Cohen, R. B., Wozney, J. M., Levitz, C. L., Shore, E. M., Zasloff, M. A., Kaplan, F. S. A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7. Genomics; 1992, 14: 759-762.

[54] Hatakeyama Y, Tuan RS, Shum L: Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis. *J Cell Biochem* 2004, 91:1204-1217.

[55] Herbert RD, Gabriel M. Effects of stretching before and after exercising on muscle soreness and risk of injury: a systematic review. BMJ. 2002 Aug 31; 325(7362):468.

[56] Hogan B. L.; Bone morphogenetic proteins: multifunctional regulators of vertebrate development. *Genes Dev.* 1996 10: 1580-1594

[57] Holderbaum D, Malemud CJ, Moskowitz RW, Haqqi TM. Human cartilage from late-stage familial Osteoarthritis transcribes type II collagen mRNA encoding a cysteine in position 519. Biochem Biophys Res Commun. 1993 May 14; 192(3):1169-74.

[58] Hunter DJ, Felson DT. Osteoarthritis. BMJ. 2006 Mar 18; 332(7542):639-42.

[59] Hwang SY, Cho ML, Park B, Kim JY, Kim YH, Min DJ, et al. Allelic frequency of MCP-1 promoter 22518 polymorphism in the Korean population and Korean patients with rheumatoid arthritis, systemic lupus erythematosus and adult-onset Still's disease. Eur J Immunogenet 2002; 29:413-16.

[60] Iikuni N, Okamoto H, Yoshio T, Sato E, Kamitsuji S, Iwamoto T, et al. Raised monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus. Ann Rheum Dis 2006; 65:253-6.

[61] James M Wilkins\*1, Lorraine Southam1, Zehra Mustafa1, Kay Chapman1 and John Loughlin2 Association of a functional microsatellite within intron 1 of the

[62] gene with susceptibility to Osteoarthritis. *BMC Medical Genetics* 2009, 10:141

[63] Jones C. M., Lyons K. M., and Hogan B. L., Involvement of Bone Morphogenetic Protein-4 (BMP-4) and *Vgr-1* in morphogenesis and neurogenesis in the mouse. Development 1991, **111**:531-542

[64] Kannu P, Bateman JF, Randle S, Cowie S, du Sart D, McGrath S, Edwards M, Savarirayan R. Premature arthritis is a distinct type II collagen phenotype. Arthritis Rheum. 2010 May; 62(5):1421-30.

[65] Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis. 1957 Dec;16(4):494-502

[66] King, J. A., P. C. Marker, K. J. Seung, and Kingsley D. M., BMP5 and the molecular, skeletal, and soft-tissue alterations in *short ear* mice. Dev. Biol. 1994 **166**:112-122

[67] King J. A., Storm E. E., Marker P. C, Dileone R. J., and. Kingsley D. M, The role of BMPs and GDFs in development of region-specific skeletal structures. Ann. NY Acad. Sci. 1996; **785**:70-79

[68] Kingsley DM. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet 1994; 10: 16-21.

[69] Kingsley D. M., The TGF-ß superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994a; **8**:133-146

[70] Knight JC: Regulatory polymorphisms underlying complex disease traits. *J Mol Med* 2005, 83:97-109.

[71] Knight PG, Glister C: (2006) TGFbeta superfamily members and ovarian follicle development. *Reproduction* 2006, 132:191-206.

[72] Knowlton RG, Katzenstein PL, Moskowitz RW, Weaver EJ, Malemud CJ, Pathria MN, Jimenez SA, Prockop DJ. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary Osteoarthritis associated with mild chondrodysplasia. N Engl J Med. 1990 Feb 22;322(8):526-30

[73] Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992; 90:772-9.

[74] Koch AE, Kunkel SL, Shah MR, Fu R, Mazarakis DD, Haines GK, et al. Macrophage inflammatory protein-1b: a C-C chemo-CHEMOKINES AND CARTILAGE DETERIORATION 1069 kine in Osteoarthritis. Clin Immunol Immunopathol 1995; 77:307-14.

[75] Largo R, Diez-Ortego I, Sanchez-Pernaute O, Lopez-Armada MJ, Alvarez-Soria MA, Egido J, et al. EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1b in synovial fibroblasts. Ann Rheum Dis 2004; 63:1197-204.

[76] Law ML, Tung L, Morse HG, Berger R, Jones C, Cheah KS, Solomon E. The human type II collagen gene (COL2A1) assigned to 12q14.3. Ann Hum Genet. 1986 May; 50(Pt 2):131-7.

[77] Leonard EJ, Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 1990; 11:97-101.

[78] Lee YH, Kim HJ, Rho YH, Choi SJ, Ji JD, Song GG. Functional polymorphisms in matrix metalloproteinase-1 and monocyte chemoattractant protein-1 and rheumatoid arthritis. Scand J Rheumatol 2003; 32:235-9.

[79] Lisignoli G, Toneguzzi S, Pozzi C, Piacentini A, Grassi F, Ferruzzi A, et al. Chemokine expression by subchondral bone marrow stromal cells isolated from Osteoarthritis (OA) and rheumatoid arthritis (RA) patients. Clin Exp Immunol 1999; 116:371-8.

[80] Loughlin J, Dowling B, Mustafa Z, et al. Association of the interleukin-1 gene cluster on chromosome 2q13 with knee osteoarthritis. Arthritis Rheum 2002;46:1519-27

[81] Luo G., Hofmann C., Bronckers A. L., Sohocki M., and Bradley A. *et al.*, BMP-7 is an inducer of nephrogenesis and is also required for eye development and skeletal patterning. Genes Dev 1995. **9**:2808-2820

[82] Lyons K. M., Pelton R. W., and Hogan B. L., Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-ß-like genes coordinately regulate aspects of embryonic development. Genes Dev1989. **3**:1657-1668

[83] Mailhot G, Yang M, Mason-Savas A, Mackay CA, Leav I, Odgren PR: BMP-5 expression increases during chondrocyte differentiation in vivo and in vitro and promotes proliferation and

**243**

*Genetics in Osteoarthritis Knee*

2008, 214:56-64.

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

in patients with Osteoarthritis. J Clin Invest. 1998 Dec 15;102(12):2115-25.

[91] Nothwang HG, Strahm B, Denich D, Kübler M, Schwabe J, Gingrich JC, et al. Molecular cloning of the interleukin-1 gene cluster: construction of an

integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13.Genomics, 1997;

[92] Oegema TR Jr, Lewis JL, Thompson

development of Osteoarthritis. Agents Actions. 1993 Nov;40(3-4):220-3.

RC Jr. Role of acute trauma in

[93] Park HJ, Yoon SH, Zheng LT, Lee KH, Kim JW, Chung JH, Lee YA, Hong SJ: Association of the 22510A/G chemokine (C–C motif) ligand two polymorphism with knee osteoarthritis

in a Korean population. Scand J Rheumatol 2007;36:299-306

Piacentini A, Silvestri T, Ruggeri R, Gualtieri G, et al. Chemokine

production by human chondrocytes. J Rheumatol 1999;26:1991-2001.

[95] Reddi AH. The interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN. Arthritis Res 2001; 3:1-5.

[96] Reddi A. H. and Huggins C., Biochemical sequences in the

[97] Rollins BJ. Chemokines. Blood

[98] Seitz M, Loetscher P, Dewald B, Towbin H, Ceska M, Baggiolini M. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins and prostaglandin E by rheumatoid and osteoarthritic

synoviocytes: regulation by IFN-gamma and IL-4. J Immunol 1994;152:2060-5.

USA 1972 69:1601-1605

1997;90:909-28

transformation of normal fibroblasts in adolescent rats. Proc. Natl. Acad. Sci.

[94] Pulsatelli L, Dolzani P,

41:370-8.

Maeda T, Tanase S, Feng L, Ohkawara S, Yoshinaga M, Yoshimura T: Production

cartilage matrix synthesis in primary chondrocyte cultures. *J Cell Physiol*

[84] Matsukawa A, Miyazaki S,

and regulation of monocyte chemoattractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis in rabbits: roles of tumour necrosis factoralpha, interleukin-1, and interleukin-8**.** *Lab Invest* 1998, 78:973-985.Scand J Rheumatol 2007;36:299-306

[85] McAlindon T, Dieppe P.

Genomics 1991; 9: 200-203.

of the hip. Arthritis Rheum

1996 May;60(Pt 3):189-99.

[88] Meulenbelt I, Williams CJ, Te Koppele JM, Van de Giessen GC, Slagboom PE. Population haplotype analysis and evolutionary relations of the COL2A1 gene. Ann Hum Genet.

[89] Moos V, Rudwaleit M, Herzog V, et al. Association of genotypes affecting the expression of interleukin- 1beta or interleukin-1 receptor antagonist with Osteoarthritis.Arthritis Rheum

[90] Nelson F, Dahlberg L, Laverty S, Reiner A, Pidoux I, Ionescu M, Fraser GL, Brooks E, Tanzer M, Rosenberg LC, Dieppe P, Robin Poole A. Evidence for the altered synthesis of type II collagen

2004;50:1179-86

2000;43: 2417-22

[87] Meulenbelt I, Seymour AB, Nieuwland M, et al. Association of the interleukin-1 gene cluster with radiographic signs of Osteoarthritis

Osteoarthritis: definitions and criteria. Ann Rheum Dis. 1989 Jul; 48(7):531-2.

[86] Mehrabian, M., Sparkes, R. S., Mohandas, T., Fogelman, A. M., Lusis, A. J. Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1.

#### *Genetics in Osteoarthritis Knee DOI: http://dx.doi.org/10.5772/intechopen.93890*

cartilage matrix synthesis in primary chondrocyte cultures. *J Cell Physiol* 2008, 214:56-64.

[84] Matsukawa A, Miyazaki S, Maeda T, Tanase S, Feng L, Ohkawara S, Yoshinaga M, Yoshimura T: Production and regulation of monocyte chemoattractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis in rabbits: roles of tumour necrosis factoralpha, interleukin-1, and interleukin-8**.** *Lab Invest* 1998, 78:973-985.Scand J Rheumatol 2007;36:299-306

[85] McAlindon T, Dieppe P. Osteoarthritis: definitions and criteria. Ann Rheum Dis. 1989 Jul; 48(7):531-2.

[86] Mehrabian, M., Sparkes, R. S., Mohandas, T., Fogelman, A. M., Lusis, A. J. Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1. Genomics 1991; 9: 200-203.

[87] Meulenbelt I, Seymour AB, Nieuwland M, et al. Association of the interleukin-1 gene cluster with radiographic signs of Osteoarthritis of the hip. Arthritis Rheum 2004;50:1179-86

[88] Meulenbelt I, Williams CJ, Te Koppele JM, Van de Giessen GC, Slagboom PE. Population haplotype analysis and evolutionary relations of the COL2A1 gene. Ann Hum Genet. 1996 May;60(Pt 3):189-99.

[89] Moos V, Rudwaleit M, Herzog V, et al. Association of genotypes affecting the expression of interleukin- 1beta or interleukin-1 receptor antagonist with Osteoarthritis.Arthritis Rheum 2000;43: 2417-22

[90] Nelson F, Dahlberg L, Laverty S, Reiner A, Pidoux I, Ionescu M, Fraser GL, Brooks E, Tanzer M, Rosenberg LC, Dieppe P, Robin Poole A. Evidence for the altered synthesis of type II collagen

in patients with Osteoarthritis. J Clin Invest. 1998 Dec 15;102(12):2115-25.

[91] Nothwang HG, Strahm B, Denich D, Kübler M, Schwabe J, Gingrich JC, et al. Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13.Genomics, 1997; 41:370-8.

[92] Oegema TR Jr, Lewis JL, Thompson RC Jr. Role of acute trauma in development of Osteoarthritis. Agents Actions. 1993 Nov;40(3-4):220-3.

[93] Park HJ, Yoon SH, Zheng LT, Lee KH, Kim JW, Chung JH, Lee YA, Hong SJ: Association of the 22510A/G chemokine (C–C motif) ligand two polymorphism with knee osteoarthritis in a Korean population. Scand J Rheumatol 2007;36:299-306

[94] Pulsatelli L, Dolzani P, Piacentini A, Silvestri T, Ruggeri R, Gualtieri G, et al. Chemokine production by human chondrocytes. J Rheumatol 1999;26:1991-2001.

[95] Reddi AH. The interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN. Arthritis Res 2001; 3:1-5.

[96] Reddi A. H. and Huggins C., Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc. Natl. Acad. Sci. USA 1972 69:1601-1605

[97] Rollins BJ. Chemokines. Blood 1997;90:909-28

[98] Seitz M, Loetscher P, Dewald B, Towbin H, Ceska M, Baggiolini M. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins and prostaglandin E by rheumatoid and osteoarthritic synoviocytes: regulation by IFN-gamma and IL-4. J Immunol 1994;152:2060-5.

[99] Sezgin M, Erdal E M, Altintas M Z, Ankarali C H, Barlas O I, Turkmen E, Sahin G: Lack of association polymorphisms of the IL1RN, IL1A, and IL1B genes with knee osteoarthritis in Turkish patients. *Clin Invest Med* 2007; 30 (2): E86-E92

[100] Smith AJ, Keen LJ, Billingham MJ, et al. Extended haplotypes and linkage disequilibrium in the IL1R1- IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 2004;5:451-60

[101] Solomon E, Hiorns LR, Spurr N, Kurkinen M, Barlow D, Hogan BL, Dalgleish R. Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family.Proc Natl Acad Sci USA.1985 May; 82(10):33304.

[102] Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, et al., Mice lacking Bmp6 function. Dev Genet 1998; 22: 321-339.

[103] Somi S, Buffing AA, Moorman AF, Van Den Hoff MJ: Dynamic patterns of expression of BMP isoforms 2, 4, 5, 6, and 7 during chicken heart development. *Anat Rec A Discov Mol Cell Evol Biol* 2004, 279:636-651.

[104] Southam L, Chapman K, Loughlin J: Genetic association analysis of *BMP5* as a potential osteoarthritis susceptibility gene. *Rheumatology,* 2003, 42:911-912.

[105] Sozzani S, Locati M, Allavena P, van Damme J, Mantovani A. Chemokines: a superfamily of chemotactic cytokines. Int J Clin Lab Res 1996; 26:69-82.

[106] Stern AG, de Carvalho MR, Buck GA, Adler RA, Rao TP, Disler D, Moxley G; I-NODAL Network. Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartilage. 2003 Jun;11(6):394-402.

[107] Thomas J. T., Lin K., Nandedkar M., Camargo M., and Cervenka J. *et al.*, A human chondrodysplasia due to a mutation in a TGF-ß superfamily member. Nat. Genet. 1996;12:315-317

[108] Urist M. R., Bone: formation by autoinduction. Science 1965: 150:893-899

[109] Volin MV, Shan MR, Tokuhira M, Haines GK, Woods JM, Koch AE. RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol 1998;89:44-53.

[110] Xu P, Yao J, Hou W. Relationships between COL2A1 gene polymorphisms and knee osteoarthritis in Han Chinese women. Mol Biol Rep. 2011 Apr; 38(4):2377-81. Epub 2010 Nov 19.

[111] Zuzarte-Luis V, Montero JA, Rodriguez-Leon J, Merino R, Rodriguez-Rey JC, Hurle JM: A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. *Dev Biol* 2004, 272:39-52

[112] Nakayama, T., M.A. Snyder, S.S. Grewal, K. Tsuneizumi, T. Tabata, and J.L. Christian. *Xenopus* Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning. *Development.*1998. 125:857-867.

[113] Parfitt AM. Quantum concept of bone remodelling and turnover: implications for the pathogenesis of osteoporosis. Calcif Tissue Int 1979; 28:1-5.

[114] Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V. Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 1997;337; 77-82.

[115] Suzuki, A., C. Chang, J.M. Yingling, X.F. Wang, and A. Hemmati-Brivanlou.

**245**

*Genetics in Osteoarthritis Knee*

2010. Vol. 62, No. 8

S30-S40.

2008;58:3132-44.

[117] White –O Connor B,

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

gene and bone mineral density. BMC

[124] Riham G.Mahfouz, Azza M. Abdu Allah, Seham A. Khodeer, Waleed F. Abd Elazeem, Mostafa Al Nagar and Walid A. Shehab-Eldin3 Frequency of Distribution of Interleukin 6 Gene 174G/C Polymorphism in obese Egyptian Cohort Journal of American

Med Genet. 2005; 6:9.

Science, 2011;7(8).

309-19.

Biol1:E69.

1:E69.

2009, 27:412-423.

[125] Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (April 1997). "Osteoprotegerin: a novel secreted protein involved in the regulation of bone density". Cell 89 (2):

[126] Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y,Christiansen C,

Jonasson K, Frigge ML,Gulcher JR, Sigurdsson G, Stefansson K 2003 Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS

[127] Styrkarsdottir U, et al. Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol. 2003;

[128] Sakao K, Takahashi KA, Arai Y, Saito M, Honjo K, Hiraoka N, Asada H, Shin-Ya M, Imanishi J, Mazda O, Kubo T: Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in Osteoarthritis. J Bone Miner Metab

[129] Sowers M, Lachance L, Jamadar D, Hochberg MC, Hollis B, Crutchfield M,

Reynisdottir I, Grant SF,

1997. Smad5 induces ventral fates in *Xenopus* embryo. *Dev. Biol*. 184:402-405.

[116] Valdes A M, Spector T D *et. al.* Genetic Variation in the *SMAD3* Gene Is Associated With Hip and Knee Osteoarthritis. Arthritis & rheumatism.

Sobal J. Nutrient intake and obesity in a multidisciplinary assessment of Osteoarthritis. Clin Thr 1986:9:

[118] Wu Q, Kim KO, Sampson ER, Chen D, Awad H, O'Brien T, et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum

[119] Yang X, Chen L, Xu X, Li C, Huang C, and Deng C. TGF-β/Smad3

Hypertrophic Differentiation and Are Required for Maintaining Articular Cartilage. The Journal of Cell Biology,

Signals Repress Chondrocyte

2001.Volume 153, Number 1

[120] Zeng Q, Huang S, Xiao Z et al.: Osteoarthritis: clinical and epidemiological investigation. Chin J

Internl Med 1995; 34: 88-90.

Rheum 1995; 38:907-16.

2005; 17:475-9.

[121] Nevitt MC, Lane NE, Scott JC, Hochberg MC, Pressman AR, Genant AK, et al., and the Study of Osteoporotic Fractures Research Group. Radiographic Osteoarthritis of the hip and bone mineral density. Arthritis

[122] Ralston SH. Genetic determinants of osteoporosis. Curr Opin Rheumatol.

[123] Reneland RH, Mah S, Kammerer S, Hoyal CR, Marnellos G, Wilson SG, Sambrook PN, Spector TD, Nelson MR,

Braun A. Association between a variation in the phosphodiesterase 4D

#### *Genetics in Osteoarthritis Knee DOI: http://dx.doi.org/10.5772/intechopen.93890*

1997. Smad5 induces ventral fates in *Xenopus* embryo. *Dev. Biol*. 184:402-405.

[116] Valdes A M, Spector T D *et. al.* Genetic Variation in the *SMAD3* Gene Is Associated With Hip and Knee Osteoarthritis. Arthritis & rheumatism. 2010. Vol. 62, No. 8

[117] White –O Connor B, Sobal J. Nutrient intake and obesity in a multidisciplinary assessment of Osteoarthritis. Clin Thr 1986:9: S30-S40.

[118] Wu Q, Kim KO, Sampson ER, Chen D, Awad H, O'Brien T, et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 2008;58:3132-44.

[119] Yang X, Chen L, Xu X, Li C, Huang C, and Deng C. TGF-β/Smad3 Signals Repress Chondrocyte Hypertrophic Differentiation and Are Required for Maintaining Articular Cartilage. The Journal of Cell Biology, 2001.Volume 153, Number 1

[120] Zeng Q, Huang S, Xiao Z et al.: Osteoarthritis: clinical and epidemiological investigation. Chin J Internl Med 1995; 34: 88-90.

[121] Nevitt MC, Lane NE, Scott JC, Hochberg MC, Pressman AR, Genant AK, et al., and the Study of Osteoporotic Fractures Research Group. Radiographic Osteoarthritis of the hip and bone mineral density. Arthritis Rheum 1995; 38:907-16.

[122] Ralston SH. Genetic determinants of osteoporosis. Curr Opin Rheumatol. 2005; 17:475-9.

[123] Reneland RH, Mah S, Kammerer S, Hoyal CR, Marnellos G, Wilson SG, Sambrook PN, Spector TD, Nelson MR, Braun A. Association between a variation in the phosphodiesterase 4D

gene and bone mineral density. BMC Med Genet. 2005; 6:9.

[124] Riham G.Mahfouz, Azza M. Abdu Allah, Seham A. Khodeer, Waleed F. Abd Elazeem, Mostafa Al Nagar and Walid A. Shehab-Eldin3 Frequency of Distribution of Interleukin 6 Gene 174G/C Polymorphism in obese Egyptian Cohort Journal of American Science, 2011;7(8).

[125] Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (April 1997). "Osteoprotegerin: a novel secreted protein involved in the regulation of bone density". Cell 89 (2): 309-19.

[126] Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y,Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML,Gulcher JR, Sigurdsson G, Stefansson K 2003 Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol1:E69.

[127] Styrkarsdottir U, et al. Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol. 2003; 1:E69.

[128] Sakao K, Takahashi KA, Arai Y, Saito M, Honjo K, Hiraoka N, Asada H, Shin-Ya M, Imanishi J, Mazda O, Kubo T: Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in Osteoarthritis. J Bone Miner Metab 2009, 27:412-423.

[129] Sowers M, Lachance L, Jamadar D, Hochberg MC, Hollis B, Crutchfield M,

et al. The associations of bone mineral density and bone turnover markers with Osteoarthritis of the hand and knee in pre- and perimenopausal women. Arthritis Rheum 1999;42:483-9.

[130] Scheidt Nave C, Bismar H, Leidig-Bruckner G, Woitge H, Seibel MJ, Ziegler R, Pfeilschifter J 2001 Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Clin Endocrinol Metab 86:2032-2042.

[131] Xiong D, Shen H, Zhao L, Xiao1 P, Yang T, Guo Y, Wang W, Guo Y, Liu Y, Recker R, Deng H. A Robust and Comprehensive Analysis of 20 Osteoporosis Candidate Genes by Very High-Density Single-Nucleotide Polymorphism Screen among 405 Caucasian Nuclear Families Identified Significant Association and Gene-Gene Interaction. J Bone Miner Res. 2006.

[132] Z.S. Özkan, D. Deveci, E. Önalan Etem and H. Yüce, Lack of effect of bone morphogenetic protein 2 and 4 gene polymorphisms on bone density in postmenopausal Turkish women Genet. Mol. Res. 9 (4): 2311-2316 (2010)

[133] Zhou Houde, BU Yanhong, Tang Aiguo, Xie Hui, Liao, Eryuan Time course of the osteoprotegerin gene expression in human primary osteoblasts as well as MG-63 cell lines and the effect of 17β-estradiol on it journal of Chinese clinical medicine volume 1 November 2 July 2006.

**247**

**Chapter 14**

**Abstract**

**1. Introduction**

Serum Hepcidin Hormone Level

This chapter sheds light on hepcidin, historical view of hepcidin, and the time of its discovery in the first section. Then this chapter gives information about the genetic aspect and the importance of gene knowledge of hepcidin in explaining many disorders in human beings, supported by illustration figures. The regulation of iron in the human body as an essential function of hepcidin is discussed in this chapter. Examples of the genes of hepcidin (HAMP and HFE) are highlighted in detail as they are essential in regulating iron as well as discussing the genetic mutations that occur in these genes and their medical and clinical impacts for many diseases such as thalassemia. Finally, the inherited disorders related to hepcidin that

**Keywords:** iron, gene mutation, HAMP gene, HFE gene, hemochromatosis

Hepcidin is presently regarded as the key to the iron balance regulator. The balance of intracellular iron is preserved by proteins that regulate iron. Hepcidin, encoded by the HAMP gene is a 25 amino acid peptide that has been lately found [1]. Several mutations in the HAMP gene have been reported. The G71D mutation is probable to be linked to reduced hepcidin activity [2]. Mutations in iron-regulating proteins cause the disorder (HFE, TfR2, and HAMP) genes. Fekri et al. showed that H63D mutation of the HFE gene could play some role in disease evolution. In iron homeostasis, the HFE gene plays a very significant role by regulating iron absorption [3]. HFE mutations are currently referred to as the reason for decreased absorption of iron, iron overload, and hereditary hemochromatosis [4]. Many types of research have shown that patients with HFE mutations in beta-thalassemia are likely to create hemochromatosis that will require early chelation of iron even in heterozygous conditions [5]. Among the mutations discovered most frequently are the three missense mutations (SNPs), which are found in the HFE gene. The most prevalent mutation within the HFE gene exon 4, leading in a shift of cysteine-totyrosine amino acid at position 282 (C282Y), 60% of hereditary hemochromatosis instances in Mediterranean populations accounted for this mutation. H63D is also a mutation leading to the replacement of histidine with aspartic acid during a C-G shift at nucleotide 187 of exon 2 of the HFE gene. In combination with the C282Y allele (C282Y/H63D), hemochromatosis is most pronounced. The HFE gene's third mutation is a substitute for 193AT in exon a pair of with an ensuing serine to cysteine replacement in amino acid position 65 (S65C) [6]. The interaction concerning

and Its Genes Polymorphism

*Safa A. Faraj and Naeem M. Al-Abedy*

lead to genetic diseases are discussed.
