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Journal of Chinese Integrative Medicine ›› 2012, Vol. 10 ›› Issue (1): 13-18.doi: 10.3736/jcim20120103

• Review • Previous Articles     Next Articles

The relationship between hypoxia-inducible factor-1α and cartilage degeneration in osteoarthritis: a review

Dong Fang-fang,Wang Yong-jun,Zhou Chong-jian()   

  1. Institute of Spine Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
  • Received:2011-08-11 Accepted:2011-10-08 Online:2012-01-20 Published:2018-09-21
  • Contact: Zhou Chong-jian

Osteoarthritis is one of the most common diseases seen in clinical practice. Cartilage survives in the hypoxic microenvironment. Hypoxia-inducible factor-1α (HIF-1α) is a key nuclear transcription factor which mediates the hypoxic response of cells. HIF-1α gene is an important regulator for the adaptation of articular cartilage to the hypoxic environment. It is important for formation of articular cartilage, energy metabolism and matrix synthesis. If the HIF-1α gene is knocked out, the cartilage can not maintain their normal morphology and function, which may lead to cartilage degeneration, and result in diseases such as osteoarthritis. Chinese herbal medicines can regulate the expression of HIF-1α gene and supply a therapy method for osteoarthritis. In this paper, the authors review the situation of the correlation between HIF-1α and osteoarthritis cartilage degeneration examined in recent years.

Key words: osteoarthritis, cartilage degeneration, hypoxia-inducible factor-1α, review

[1] Alcaraz MJ, Megías J, García-Arnandis I, Clérigues V, Guillén MI . New molecular targets for the treatment of osteoarthritis. Biochem Pharmacol. 2010 ; 80(1):13-21.
doi: 10.1016/j.bcp.2010.02.017 pmid: 13
[2] Ramakrishnan P, Hecht BA, Pedersen DR, Lavery MR, Maynard J, Buckwalter JA, Martin JA . Oxidant conditioning protects cartilage from mechanically induced damage.J Orthop Res. 2010; 28(7):914-920.
doi: 10.1002/jor.21072 pmid: 20058262
[3] Stokes DG, Liu G, Coimbra IB, Piera-Velazquez S, Crowl RM, Jiménez SA . Assessment of the gene expression profile of differentiated and dedifferentiated human fetal chondrocytes by microarray analysis. Arthritis Rheum. 2002; 46(2) : 404-419.
doi: 10.1002/art.v46:2
[4] Ueki M, Tanaka N, Tanimoto K, Nishio C, Honda K, Lin YY, Tanne Y, Ohkuma S, Kamiya T, Tanaka E, Tanne K . The effect of mechanical loading on the metabolism of growth plate chondrocytes. Ann Biomed Eng. 2008; 36(5):793-800.
doi: 10.1007/s10439-008-9462-7
[5] Sanchez CP . Growth-plate cartilage in chronic renal failure. Pediatr Nephrol. 2010; 25(4):643-649.
doi: 10.1007/s00467-009-1307-6 pmid: 19816714
[6] Gibson JS , McCartney D, Sumpter J, Fairfax TP, Milner PI, Edwards HL, Wilkins RJ. Rapid effects of hypoxia on H + homeostasis in articular chondrocytes . Pflugers Arch. 2009; 458(6):1085-1092.
doi: 10.1007/s00424-009-0695-6 pmid: 19629519
[7] Huang LE, Gu J, Schau M, Bunn HF . Regulation of hypoxia-inducible factor la is mediated by an 02-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. 1998; 95(14):7987-7992.
doi: 10.1073/pnas.95.14.7987
[8] Salceda S, Caro J . Hypoxia-inducible factor lα( HIF- lα) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997; 272(36):22642-22647.
doi: 10.1074/jbc.272.36.22642
[9] Hofer T, Desbaillets I, Höpfl G, Gassmann M, Wenger RH . Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-la activation cascade: implications for HIF-1 a gene therapy. FASEB J. 2001; 15(14):2715-2717.
doi: 10.1096/fj.01-0546fje
[10] Semenza GL . Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis.J Lab Clin Med. 1998; 131(3) : 207-214.
doi: 10.1016/S0022-2143(98)90091-9 pmid: 9523843
[11] Semenza GL . HIF-1 and human disease: one highly involved factor. Genes Dev. 2000; 14(16):1983-1991.
[12] Semenza GL . Regulation of mammalian 02 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999; 15:551-578.
doi: 10.1146/annurev.cellbio.15.1.551
[13] Grimmer C, Pfander D, Swoboda B, Aigner T, Mueller L, Hennig FF, Gelse K . Hypoxia-inducible factor lα is involved in the prostaglandin metabolism of osteoarthritic cartilage through up-regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes. Arthritis Rheum. 2007; 56(12):4084-4094.
doi: 10.1002/art.v56:12
[14] Yudoh K, Nakamura H, Masuko-Hongo K, Kato T, Nishioka K . Catabolic stress induces expression of hypoxia-inducible factor (HIF)-lα in articular chondrocytes: involvement of HIF-1α in the pathogenesis of osteoarthritis .Arthritis Res Ther. 2005; 7(5) : 225.
doi: 10.1186/ar1822
[15] Pfander D, Cramer T, Swoboda B . Hypoxia and HIF- lα in osteoarthritis. Int Orthop. 2005; 29(1) : 6-9.
doi: 10.1007/s00264-004-0618-2
[16] Schneider U, Miltner O, Thomsen M , Graf J, Niethard FU. Intra-articular oxygen partial pressure measurements under functional conditions. Z Orthop Ihre Grenzgeb. 1996; 134(5) : 422-425. German with abstract in English.
doi: 10.1055/s-2008-1037431 pmid: 8967141
[17] Semenza GL, Wang GL . A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992 ; 12(12) : 5447-5454.
doi: 10.1128/MCB.12.12.5447
[18] Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL . Activation of vascular endothelial growth factor gene transcription by hypoxia- inducible factor 1. Mol Cell Biol. 1996; 16(9):4604-4613.
doi: 10.1128/MCB.16.9.4604
[19] Li FX, Quan Y, Xia QM. Hypoxia-inducible factor and the mechanism of hypoxia regulatory. Zhongguo Lin Chuang Kang Fu. 2004; 8(30):6744-6746. Chinese.
李福祥, 全燕, 夏前明 . 低氧诱导因子及其低氧调节机制.中国临床康复. 2004; 8(30):6744-6746.
[20] Sun X, Wei Y . The role of hypoxia-inducible factor in osteogenesis and chondrogenesis. Cy to therapy. 2009 ; 11(3) : 261-267.
doi: 10.1080/14653240902824765 pmid: 19308769
[21] Tanaka E , Aoyama J, Miyauchi M, Takata T, Hanaoka K, Iwabe T, Tanne K. Vascular endothelial growth factor plays an important autocrine/paracrine role in the progression of osteoarthritis. Histochem Cell Biol. 2005; 123(3) : 275-281.
doi: 10.1007/s00418-005-0773-6
[22] Murata M, Yudoh K, Nakamura H, Kato T, Inoue K, Chiba J, Nishioka K, Masuko-Hongo K . Distinct signaling pathways are involved in hypoxia- and IL-1- induced VEGF expression in human articular chondrocytes. J Orthop Res. 2006; 24(7):1544-1554.
[23] Sato F, Bhawal UK, Kawamoto T, Fujimoto K, Imaizumi T, Imanaka T, Kondo J, Koyanagi S, Noshiro M, Yoshida H , KusumiT, Kato Y, Kijima H. Basic-helix- loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression. Genes Cells. 2008; 13(2):131-144.
doi: 10.1111/j.1365-2443.2007.01153.x
[24] De Spiegelaere W, Cornillie P , Van den Broeck W. Localization of erythropoietin in and around growing cartilage. Mol Cell Biochem. 2010; 337(1-2):287-291.
doi: 10.1007/s11010-009-0310-3 pmid: 19908127
[25] Coimbra IB, Jimenez SA, Hawkins DF, Piera-Velazquez S, Stokes DG . Hypoxia inducible factor-lα expression in human normal and osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2004; 12(4):336-345.
doi: 10.1016/j.joca.2003.12.005 pmid: 15023385
[26] Zhu G, Tang Y, Liang X, Zheng M, Yang J, Zhou H, Li L, Qin T . Role of hypoxia-inducible factor-lα in the regulation of plasminogen activator activity in rat knee joint chondrocytes. Osteoarthritis Cartilage. 2009 ; 17(11) : 1494-1502.
doi: 10.1016/j.joca.2009.05.005
[27] Kuo HP, Lee DF, Xia W, Wei Y, Hung MC . TNFα induces HIF-la expression through activation of IKKp. Biochem Biophys Res Commun. 2009; 389(4):640-644.
doi: 10.1016/j.bbrc.2009.09.042
[28] Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS . Hypoxia in cartilage: HIF-lα is essential for chondrocyte growth arrest and survival. Genes Dev. 2001; 15(21):2865-2876.
[29] Gelse K, Pfander D, Obier S, Knaup KX, Wiesener M, Hennig FF, Swoboda B . Role of hypoxia-inducible factor la in the integrity of articular cartilage in murine knee joints. Arthritis Res Ther. 2008; 10(5):R111.
doi: 10.1186/ar2508
[30] Kim HK, Bian H , Aya-ay J, Garces A, Morgan EF, Gilbert SR. Hypoxia and HIF-lα expression in the epiphyseal cartilage following ischemic injury to the immature femoral head. Bone. 2009; 45(2):280-288.
doi: 10.1016/j.bone.2009.03.665
[31] Pfander D, Gelse K . Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr Opin Rheumatol. 2007; 19(5):457-462.
doi: 10.1097/BOR.0b013e3282ba5693 pmid: 17762611
[32] Pina-Oviedo S, Khalili K, Del Valle L . Hypoxia inducible factor-la activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy. Acta Neuropathol. 2009; 118(2):235-247.
doi: 10.1007/s00401-009-0533-0
[33] Genin O, Hasdai A, Shinder D, Pines M . Hypoxia, hypoxia-inducible factor-lα( HIF-lα), and heat-shock proteins in tibial dyschondroplasia. Poult Sci. 2008; 87(8):1556-1564.
doi: 10.3382/ps.2008-00124
[34] Zinkernagel AS, Johnson RS, Nizet V . Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med (Berl). 2007; 85(12):1339-1346.
doi: 10.1007/s00109-007-0282-2 pmid: 18030436
[35] Araldi E, Schipani E . Hypoxia, HIFs and bone development. Bone. 2010; 47(2):190-196.
doi: 10.1016/j.bone.2010.04.606 pmid: 2902564
[36] Malladi P, Xu Y, Chiou M, Giaccia AJ, Longaker MT . Hypoxia inducible factor-lα deficiency affects chondrogenesis of adipose-derived adult stromal cells. Tissue Eng. 2007; 13(6):1159-1171.
doi: 10.1089/ten.2006.0265
[37] Brucker PU, Izzo NJ, Chu CR . Tonic activation of hypoxia-inducible factor la in avascular articular cartilage and implications for metabolic homeostasis. Arthritis Rheum. 2005; 52(10):3181-3191.
doi: 10.1002/(ISSN)1529-0131
[38] Jones NM, Lee EM, Brown TG, Jarrott B, Beart PM . Hypoxic preconditioning produces differential expression of hypoxia-inducible factor-lα( HIF-lα) and its regulatory enzyme HIF prolyl hydroxylase 2 in neonatal rat brain. Neurosci Lett. 2006; 404(1-2):72-77.
doi: 10.1016/j.neulet.2006.05.049
[39] Kanichai M, Ferguson D, Prendergast PJ, Campbell VA . Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: a role for AKT and hypoxia-inducible factor (HIF)-lα. J Cell Physiol. 2008; 216(3):708-715.
doi: 10.1002/jcp.v216:3
[40] Duval E, Leclercq S, Elissalde JM, Demoor M, Galéra P, Boumédiene K . Hypoxia-inducible factor lα inhibits the fibroblast-like markers type Ⅰ and type Ⅲ collagen during hypoxia-induced chondrocyte redifferentiation : hypoxia not only induces type II collagen and aggrecan, but it also inhibits type Ⅰ and type Ⅲ collagen in the hypoxia-inducible factor lα-dependent redifferentiation of chondrocytes. Arthritis Rheum. 2009 ; 60(10 ): 3038-3048.
doi: 10.1002/art.v60:10
[41] Chen CW , Chen YQ. Experiment research on the influence of Yanghe decoction on the expression of HIF-lα mRNA in osteoarthritis. Zhongguo Gu Shang. 2008; 21(6):432-434. Chinese with abstract in English.
陈朝蔚, 陈永强 . 阳和汤对骨关节炎软骨细胞HIF-la mRNA影响的实验研究.中国骨伤. 2008; 21(6):432-434.
[42] Han QM. To study the molecular biology mechanism of the pathological change of knee osteoarthritis cartilage and intervention by Chinese herb. Guangzhou: Guangzhou University of Chinese Medicine. 2006. Chinese with abstract in English.
doi: 10.7666/d.y916149
韩清民 . 膝骨关节炎软骨病理改变的分子生物学机制及中药干预研究. 广州: 广州中医药大学. 2006.
doi: 10.7666/d.y916149
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