Role of HIF-1α signaling pathway in osteoarthritis: a systematic review

Fernández-Torres, Javier; Martínez-Nava, Gabriela Angélica; Gutiérrez-Ruíz, María Concepción; Gómez-Quiroz, Luis Enrique; Gutiérrez, Marwin

doi:10.1016/j.rbre.2016.07.008

Javier Fernández-Torres ^**Corresponding author. E-mail: javier_astrofan@hotmail.com (J. Fernández-Torres).

Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Laboratorio de Líquido Sinovial, Mexico City, Mexico

Universidad Autónoma Metropolitana Iztapalapa, Programa de Doctorado de Ciencias Biológicas y de la Salud, Mexico City, Mexico

Gabriela Angélica Martínez-Nava

Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Laboratorio de Líquido Sinovial, Mexico City, Mexico

María Concepción Gutiérrez-Ruíz

Universidad Autónoma Metropolitana Iztapalapa, Programa de Doctorado de Ciencias Biológicas y de la Salud, Mexico City, Mexico

Luis Enrique Gómez-Quiroz

Universidad Autónoma Metropolitana Iztapalapa, Programa de Doctorado de Ciencias Biológicas y de la Salud, Mexico City, Mexico

Marwin Gutiérrez

Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Laboratorio de Líquido Sinovial, Mexico City, Mexico

Universidad Autónoma Metropolitana Iztapalapa, Programa de Doctorado de Ciencias Biológicas y de la Salud, Mexico City, Mexico

*Corresponding author. E-mail: javier_astrofan@hotmail.com (J. Fernández-Torres).

Conflict of interest

The authors declare no conflicts of interest.

Figures (5)
Tables (2)

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Fig. 1
Representation of the search strategy.

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Fig. 2
Structure of hypoxia inducible factor 1-α (HIF-1α). The NH2-terminal of HIF-1α and HIF-1β consists of bHLH (basic helix–loop–helix) and PAS (Per-ARNT-Sim homology) domains that are required for heterodimerization and DNA binding. The COOH-terminal of HIF-1α (residues 531–826) contains two transactivation domains (TADs). The short half-life of HIF-1α under nonhypoxic and posthypoxic conditions is due to rapid ubiquitination and proteasomal degradation. HIF-1α residues 400–600, this region was designated the oxygen-dependent degradation domain (ODDD).

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Fig. 3
HIF-1α activity under normoxic conditions. Under normoxia conditions, the specific proline residues 402 and 564 on ODDD domain are hydroxylated by oxygen dependent prolyl-hydroxylases (PHDs) that leads to the formation of a complex with the von Hippel-Lindau (VHL) factor; which in turn, binds to ubiquitin (Ub) and is subsequently degraded by the proteasome.

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Fig. 4
HIF-1α activity under hypoxic conditions. Under hypoxic conditions, HIF-1α is stabilized and phosphorylated by MAPK; once phosphorylated, HIF-1α translocates to the nucleus and binds to HIF-1β subunit to form the [HIF-1α/HIF-1β] complex. This complex, through the HRE, binds to specific DNA sequence 5′TAGCGTGH3′ present in the promoter regions of several genes for their subsequent activation.

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Fig. 5
The presence of rs11549465 polymorphism, generates a change of proline by serine, which confers greater stability to the HIF-1α protein due to poor interaction between VHL and hydroxylation sites within the ODDD.

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Table 1
Genes associated with the development of OA.

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Table 2
Single nucleotide polymorphisms (SNP) associated with OA processes.

Gene	Chromosome	Phenotypic manifestation
COL2A1, COL11A1, COL11A2	1, 6, 12	Early onset OA
COL9A1	6	Early onset of knee OA
MATN3	2	Early onset of hand and knee OA
COMP	19	Early onset of hip OA hip
COL1A1	17	Reduction of hip OA in women
BMP2	20	Reduction of knee OA in women
TGFB1	19	OA
FRZB, IL4R	2, 16	Hip OA in women
IL1, ASPN, TIMP3	2, 9, 22	Hip and knee OA
IL6	7	Hip OA
AGC1	15	Hand OA
VDR	12	Arthritis in several joints
ERA	6	OA in women
ADAM12, LRCH1, TNA	3, 10, 13	Knee OA
CILP	15	Knee OA in men
CALM1	14	Hip OA in Japanese population
IGF-1	12	Increased risk of OA
IL17	6	Susceptibility to develop OA

Gene/dbSNP rs Id	Phenotype	First author [Reference]
WISP1 rs2929970	Susceptibility to spinal OA in woman	Urano et al.²⁵25 Urano T, Narusawa K, Hosoi T, Ouchi Y, Nakamura T, Inoue S. Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women. J Bone Miner Metab. 2007;25:253-8.
RAGE rs2070600	Susceptibility to knee OA	Han et al.²⁶26 Han Z, Liu Q, Sun C, Li Y. The interaction between obesity and RAGE polymorphisms on the risk of knee osteoarthritis in Chinese population. Cell Physiol Biochem. 2012;30:898-904.
DVWA rs7639618	Susceptibility to knee OA	Zhang et al.²⁷27 Zhang R, Yao J, Xu P, Ji B, Voegeli G, Hou W, et al. Association between genetic variants of DVWA and osteoarthritis of the knee and hip: a comprehensive meta-analysis. Int J Clin Exp Med. 2015;8:9430-7.
ACE rs4343, rs4362	Susceptibility to knee OA	Qing et al.²⁸28 Qing Z, Ye J. Association between ACE polymorphisms and osteoarthritis susceptibility. Int J Clin Exp Pathol. 2015;8:7391-6.
MATN3 rs8176070	Susceptibility to OA	Gu et al.²⁹29 Gu J, Rong J, Guan F, Jiang L, Tao S, Guan G, et al. MATN3 gene polymorphism is associated with osteoarthritis in Chinese han population: a community-based case–control study. Scientific World J. 2012;2012:656084.
DIO2 rs225014	Susceptibility to OA	Meulenbelt et al.³⁰30 Meulenbelt I, Min J, Bos S, Riyazi N, Houwing J, Slagboom E, et al. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum Mol Genet. 2008;17:1867-75.
ADAMTS14 rs4747096	knee OA in woman (Thai population)	Poonpet et al.³¹31 Poonpet T, Honsawek S, Tammachote N, Kanitnate S, Tammachote R. ADAMTS14 gene polymorphism associated with knee osteoarthritis in Thai women. Genet Mol Res. 2013;12:5301-9.
ADAM12 rs1871054	Increased risk of OA	Wang et al.³²32 Wang L, Guo L, Tian F, Hao R, Yang T. Analysis of single nucleotide polymorphisms within ADAM12 and risk of knee osteoarthritis in a Chinese Han population. Biomed Res Int. 2015;2015:518643.; Kerna et al.³³33 Kerna I, Kisand K, Tamm AE, Kumm J, Tamm AO. Two single-nucleotide polymorphisms in ADAM12 gene are associated with early and late radiographic knee osteoarthritis in Estonian population. Arthritis. 2013;2013:878126.
HIF1A rs11549465	Protective role in the loss of articular cartilage	Fernández et al.³⁴34 Fernández-Torres J, Hernández-Díaz C, Espinosa-Morales R, Camacho-Galindo J, Galindo-Sevilla Ndel C, López-Macay A, et al. Polymorphic variation of hypoxia inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study. BMC Musculoskelet Disord. 2015;16:218.
IL6 rs1800796	Protective factor for hip and knee OA in the elderly	Fernandes et al.³⁵35 Fernandes MT, Fernandes KB, Marquez AS, Cólus IM, Souza MF, Santos JP, et al. Association of interleukin-6 gene polymorphism (rs1800796) with severity and functional status of osteoarthritis in elderly individuals. Cytokine. 2015;75:316-20.
IL16 rs11556218, rs4072111, rs4778889	Decreased knee OA risk	Luo et al.³⁶36 Luo SX, Li S, Zhang XH, Zhang JJ, Long GH, Dong GF, et al. Genetic polymorphisms of interleukin-16 and risk of knee osteoarthritis. PLoS One. 2015;10:e0123442.; Liu et al.³⁷37 Liu Z, Ma L, Qiu S, Jia T. Genetic polymorphisms of interleukin-16 are associated with susceptibility to primary knee osteoarthritis. Int J Clin Exp Med. 2015;8:1401-1405, eCollection 2015.
GDF5 rs143383	Protective factor for knee OA	Pan et al.³⁸38 Pan F, Tian J, Winzenberg T, Ding C. Association between GDF5 rs143383 polymorphism and knee osteoarthritis: an updated meta-analysis based on 23,995 subjects. BMC Musculoskelet Disord. 2014;15:404.; Tawonsawatruk et al.³⁹39 Tawonsawatruk T, Changthong T, Pingsuthiwong S, Trachoo O, Saura T, Wajanavisit W. A genetic association study between growth differentiation factor (GDF5) polymorphism and knee osteoarthritis in Thai population. J Orthopaed Surg. 2011;Res6:2-5.

[1] *Corresponding author. E-mail: javier_astrofan@hotmail.com (J. Fernández-Torres).

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Role of HIF-1α signaling pathway in osteoarthritis: a systematic review

Abstract