Skip to main content

Hormones and growth factors in the pathogenesis of spinal ligament ossification

European Spine Journal volume 16, pages 1075–1084 (2007)Cite this article

Abstract

Ossification of the spinal ligaments (OSL) is a pathologic condition that causes ectopic bone formation and subsequently results in various degrees of neurological deficit, but the etiology of OSL remains almost unknown. Some systemic hormones, such as 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), insulin and leptin, and local growth factors, such as transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP), have been studied and are thought to be involved in the initiation and development of OSL. This review article summarizes these studies, delineates the possible mechanisms, and puts forward doubts and new questions. The related findings from studies of genes and target cells in the ligament of OSL are also discussed. Although these findings may be helpful in understanding the pathogenesis of OSL, much more research needs to be conducted in order to investigate the nature of OSL.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Adams JE, Davies M (1977) Paravertebral and peripheral ligamentous ossification: an unusual association of hypoparathyroidism. Postgrad Med J 53:167–172

    PubMed  CAS  Article  Google Scholar 

  2. Akune T, Ogata N, Seichi A, Ohnishi I, Nakamura K, Kawaguchi H (2001) Insulin secretory response is positively associated with the extent of ossification of the posterior longitudinal ligament of the spine. J Bone Joint Surg Am 83:1537–1544

    PubMed  Google Scholar 

  3. Altomonte L, Zoli A, Mirone L, Marchese G, Scolieri P, Barini A, Magaro M (1992) Growth hormone secretion in diffuse idiopathic skeletal hyperostosis. Ann Ital Med Int 7:30–33

    PubMed  CAS  Google Scholar 

  4. Bobacz K, Ullrich R, Amoyo L, Erlacher L, Smolen JS, Graninger WB (2006) Stimulatory effects of distinct members of the bone morphogenetic protein family on ligament fibroblasts. Ann Rheum Dis 65:169–177

    PubMed  Article  CAS  Google Scholar 

  5. Bussiere JL, Ristori JM, Miravet L, Piat C, Soubrier M, Bardin T (1993) Vitamin-resistant hypophosphatemic rickets and spinal cord compression: apropos of 2 cases. Rev Rhum Ed Fr 60:64–68

    PubMed  CAS  Google Scholar 

  6. Chen NX, Moe SM (2003) Arterial calcification in diabetes. Curr Diab Rep 3:28–32

    PubMed  Article  Google Scholar 

  7. Choi S, Lee SH, Lee JY, Choi WG, Choi WC, Choi G, Jung B, Lee SC (2005) Factors affecting prognosis of patients who underwent corpectomy and fusion for treatment of cervical ossification of the posterior longitudinal ligament: analysis of 47 patients. J Spinal Disord Tech 18:309–314

    PubMed  Article  Google Scholar 

  8. Coaccioli S, Fatati G, Di Cato L, Marioli D, Patucchi E, Pizzuti C, Ponteggia M, Puxeddu A (2000) Diffuse idiopathic skeletal hyperostosis in diabetes mellitus, impaired glucose tolerance and obesity. Panminerva Med 42:247–251

    PubMed  CAS  Google Scholar 

  9. Daragon A, Mejjad O, Czernichow P, Louvel JP, Vittecoq O, Durr A, Le Loet X (1995) Vertebral hyperostosis and diabetes mellitus: a case-control study. Ann Rheum Dis 54:375–378

    PubMed  CAS  Google Scholar 

  10. Denko CW, Boja B, Malemud CJ (2002) Growth hormone and insulin-like growth factor-I in symptomatic and asymptomatic patients with diffuse idiopathic skeletal hyperostosis (DISH). Front Biosci 7:37–43

    Article  Google Scholar 

  11. Denko CW, Boja B, Moskowitz RW (1994) Growth promoting peptides in osteoarthritis and diffuse idiopathic skeletal hyperostosis–insulin, insulin-like growth factor-I, growth hormone. J Rheumatol 21:1725–1730

    PubMed  CAS  Google Scholar 

  12. Denko CW, Malemud CJ (2005) Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin Arthritis Rheum 35:24–34

    PubMed  Article  CAS  Google Scholar 

  13. Denko CW, Malemud CJ (2006) Body mass index and blood glucose: correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int 26:292–297

    PubMed  Article  CAS  Google Scholar 

  14. DiGiovanna JJ, Helfgott RK, Gerber LH, Peck GL (1986) Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. N Engl J Med 315:1177–1182

    PubMed  CAS  Article  Google Scholar 

  15. Ducy P, Schinke T, Karsenty G (2000) The osteoblast: a sophisticated fibroblast under central surveillance. Science 289:1501–1504

    PubMed  Article  CAS  Google Scholar 

  16. Feng JQ, Harris MA, Ghosh-Choudhury N, Feng M, Mundy GR, Harris SE (1994) Structure and sequence of mouse bone morphogenetic protein-2 gene (BMP-2): comparison of the structures and promoter regions of BMP-2 and BMP-4 genes. Biochim Biophys Acta 1218:221–224

    PubMed  CAS  Google Scholar 

  17. Feng JQ, Chen D, Cooney AJ, Tsai MJ, Harris MA, Tsai SY, Feng M, Mundy GR, Harris SE (1995) The mouse bone morphogenetic protein-4 gene. Analysis of promoter utilization in fetal rat calvarial osteoblasts and regulation by COUP-TFI orphan receptor. J Biol Chem 270:28364–28373

    PubMed  Article  CAS  Google Scholar 

  18. Furushima K, Shimo-Onoda K, Maeda S, Nobukuni T, Ikari K, Koga H, Komiya S, Nakajima T, Harata S, Inoue I (2002) Large-scale screening for candidate genes of ossification of the posterior longitudinal ligament of the spine. J Bone Miner Res 17:128–137

    PubMed  Article  CAS  Google Scholar 

  19. Goto K, Yamazaki M, Tagawa M, Goto S, Kon T, Moriya H, Fujimura S (1998) Involvement of insulin-like growth factor I in development of ossification of the posterior longitudinal ligament of the spine. Calcif Tissue Int 62:158–165

    PubMed  Article  CAS  Google Scholar 

  20. Harata S, Kawagishi T (1979) The ossification of the posterior longitudinal ligament of the cervical spine in diabetes. In: Japanese Ministry of Public Health and Welfare (ed) Investigation committee report on the ossification of the spinal ligaments of the Japanese ministry of public health and welfare in 1978. Tokyo, pp 27–28

  21. Hayashi K, Ishidou Y, Yonemori K, Nagamine T, Origuchi N, Maeda S, Imamura T, Yoshida H, Sampath TK, ten Dijke P, Sakou T (1997) Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossification of the ligamentum flavum. Bone 21:23–30

    PubMed  Article  CAS  Google Scholar 

  22. Highman JH, Sanderson PH, Sutcliffe MM (1970) Vitamin-D-resistant osteomalacia as a cause of cord compression. Q J Med 39:529–537

    PubMed  CAS  Google Scholar 

  23. Hirakawa H, Kusumi T, Nitobe T, Ueyama K, Tanaka M, Kudo H, Toh S, Harata S (2004) An immunohistochemical evaluation of extracellular matrix components in the spinal posterior longitudinal ligament and intervertebral disc of the tiptoe walking mouse. J Orthop Sci 9:591–597

    PubMed  Article  CAS  Google Scholar 

  24. Honda H (1983) Histopathological study of aging of the posterior portion of human cervical vertebral bodies and discs-with special reference to the early ossification of the posterior longitudinal ligament. Nippon Seikeigeka Gakkai Zasshi 57:1881–1893

    PubMed  CAS  Google Scholar 

  25. Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, Hirabayashi S, Sugimori K, Matsumoto M, Kawaguchi H, Takahashi M, Inoue H, Kimura T, Matsusue Y, Inoue I, Baba H, Nakamura K, Ikegawa S (2006) A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. Hum Genet 119:611–616

    PubMed  Article  Google Scholar 

  26. Hoshi K, Amizuka N, Sakou T, Kurokawa T, Ozawa H (1997) Fibroblasts of spinal ligaments pathologically differentiate into chondrocytes induced by recombinant human bone morphogenetic protein-2: morphological examinations for ossification of spinal ligaments. Bone 21:155–162

    PubMed  Article  CAS  Google Scholar 

  27. Ikegawa S, Kurokawa T, Hizuka N, Hoshino Y, Ohnishi I, Shizume K (1993) Increase of serum growth hormone-binding protein in patients with ossification of the posterior longitudinal ligament of the spine. Spine 18:1757–1760

    PubMed  CAS  Article  Google Scholar 

  28. Imamura T, Sakou T, Matsunaga S, Taketomi E, Ishido Y, Yoshida H (1995) Histochemical and immunohistochemical study on the skin of patients with ossification of the posterior longitudinal ligament in the cervical spine. In Vivo 9:167–171

    PubMed  CAS  Google Scholar 

  29. Inaba K, Matsunaga S, Ishidou Y, Imamura T, Yoshida H (1996) Effect of transforming growth factor-β on fibroblasts in ossification of the posterior longitudinal ligament. In Vivo 10:445–449

    PubMed  CAS  Google Scholar 

  30. Inaba T, Ishibashi S, Gotoda T, Kawamura M, Morino N, Nojima Y, Kawakami M, Yazaki Y, Yamada N (1996) Enhanced expression of platelet-derived growth factor-β receptor by high glucose: involvement of platelet-derived growth factor in diabetic angiopathy. Diabetes 45:507–512

    PubMed  Article  CAS  Google Scholar 

  31. Inamasu J, Guiot BH, Sachs DC (2006) Ossification of the posterior longitudinal ligament: an update on its biology, epidemiology and natural history. Neurosurgery 58:1027–1039

    PubMed  Article  Google Scholar 

  32. Ishida Y, (1988) Studies on induction mechanism of ossification of the posterior longitudinal of the spine:especially on the cultured cells from the human spinal ligament. J Jpn Orthop Assoc 62:1019–1027 (in Japanese)

    Google Scholar 

  33. Ishida Y, Kawai S (1993) Characterization of cultured cells derived from ossification of the posterior longitudinal ligament of the spine. Bone 14:85–91

    PubMed  Article  CAS  Google Scholar 

  34. Ishida Y, Kawai S (1993) Effects of bone-seeking hormones on DNA synthesis, cyclic AMP level, and alkaline phosphatase activity in cultured cells from human posterior longitudinal ligament of the spine. J Bone Miner Res 8:1291–1300

    PubMed  CAS  Article  Google Scholar 

  35. Ishidou Y, Tokunaga M, Murata F, Yoshida H, Sakou T (1995) Expression of decorin mRNA in the skin of patients with ossification of the posterior longitudinal ligament. In Vivo 9:469–474

    PubMed  CAS  Google Scholar 

  36. Ishizawa N (1992) Experimental study of hyperostosis induced by hypervitaminosis A. J Jpn Orthop Assoc 66:919–930 (in Japanese)

    Google Scholar 

  37. Julkunen H, Karava R, Viljanen V (1966) Hyperostosis of the spine in diabetes mellitus and acromegaly. Diabetologia 2:123–126

    PubMed  Article  CAS  Google Scholar 

  38. Julkunen H, Pyorala K, Lehtovirta E (1968) Hyperostosis of the spine in relation to age and hyperglycemia in men aged 30–69. Ann Med Intern Fenn 57:1–7

    PubMed  CAS  Google Scholar 

  39. Kamiya M, Harada A, Mizuno M, Iwata H, Yamada Y (2001) Association between a polymorphism of the transforming growth factor-β1 gene and genetic susceptibility to ossification of the posterior longitudinal ligament in Japanese patients. Spine 26:1264–1266

    PubMed  Article  CAS  Google Scholar 

  40. Kawaguchi H, Kurokawa T, Hoshino Y, Kawahara H, Ogata E, Matsumoto T (1992) Immunohistochemical demonstration of bone morphogenetic protein-2 and transforming growth factor-β in the ossification of the posterior longitudinal ligament of the cervical spine. Spine 17(Suppl 3):S33–S36

    PubMed  CAS  Article  Google Scholar 

  41. Kawaguchi Y, Furushima K, Sugimori K, Inoue I, Kimura T (2003) Association between polymorphism of the transforming growth factor-β1 gene with the radiologic characteristic and ossification of the posterior longitudinal ligament. Spine 28:1424–1426

    PubMed  Article  Google Scholar 

  42. Kiss C, Szilagyi M, Paksy A, Poor G (2002) Risk factors for diffuse idiopathic skeletal hyperostosis: a case-control study. Rheumatology 41:27–30

    PubMed  Article  CAS  Google Scholar 

  43. Kobashi G, Washio M, Okamoto K, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N, Ohta K, Inaba Y, Tanaka H (2004) High body mass index after age 20 and diabetes mellitus are independent risk factors for ossification of the posterior longitudinal ligament of the spine in Japanese subjects: a case-control study in multiple hospitals. Spine 29:1006–1010

    PubMed  Article  Google Scholar 

  44. Kodama T, Matsunaga S, Taketomi E, Sakou T (1998) Retinoid and bone metabolic marker in ossification of the posterior longitudinal ligament. In Vivo 12:339–344

    PubMed  CAS  Google Scholar 

  45. Koga H, Hayashi K, Taketomi E, Matsunaga S, Yashiki S, Fujiyoshi T, Sonoda S, Sakou T (1996) Restriction fragment length polymorphism of genes of the α2(XI) collagen, bone morphogenetic protein-2, alkaline phosphatase, and tumor necrosis factor-α among patients with ossification of posterior longitudinal ligament and controls from the Japanese population. Spine 21:469–473

    PubMed  Article  CAS  Google Scholar 

  46. Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED (1998) High glucose-induced transforming growth factor β1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest 101:160–169

    PubMed  CAS  Article  Google Scholar 

  47. Kon T, Yamazaki M, Tagawa M, Goto S, Terakado A, Moriya H, Fujimura S (1997) Bone morphogenetic protein-2 stimulates differentiation of cultured spinal ligament cells from patients with ossification of the posterior longitudinal ligament. Calcif Tissue Int 60:291–296

    PubMed  Article  CAS  Google Scholar 

  48. Kosaka T, Imakiire A, Mizuno F, Yamamoto K (2000) Activation of nuclear factor kappaB at the onset of ossification of the spinal ligaments. J Orthop Sci 5:572–578

    PubMed  Article  CAS  Google Scholar 

  49. Lam S, van der Geest RN, Verhagen NA, van Nieuwenhoven FA, Blom IE, Aten J, Goldschmeding R, Daha MR, van Kooten C (2003) Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 52:2975–2983

    PubMed  Article  CAS  Google Scholar 

  50. Lam S, Verhagen NA, Strutz F, van der Pijl JW, Daha MR, van Kooten C (2003) Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1. Kidney Int 63:878–888

    PubMed  Article  CAS  Google Scholar 

  51. Lee CY, Liu X, Smith CL, Zhang X, Hsu HC, Wang DY, Luo ZP (2004) The combined regulation of estrogen and cyclic tension on fibroblast biosynthesis derived from anterior cruciate ligament. Matrix Biol 23:323–329

    PubMed  Article  CAS  Google Scholar 

  52. Littlejohn GO, Smythe HA (1981) Marked hyperinsulinemia after glucose challenge in patients with diffuse idiopathic skeletal hyperostosis. J Rheumatol 8:965–968

    PubMed  CAS  Google Scholar 

  53. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P (1993) Function of retinoic acid receptor gamma in the mouse. Cell 73:643–658

    PubMed  Article  CAS  Google Scholar 

  54. Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P (1994) Function of the retinoic acid receptors (RARs) during development (I): craniofacial and skeletal abnormalities in RAR double mutants. Development 120:2723–2748

    PubMed  CAS  Google Scholar 

  55. Marui T, Niyibizi C, Georgescu HI, Cao M, Kavalkovich KW, Levine RE, Woo SL (1997) Effect of growth factors on matrix synthesis by ligament fibroblasts. J Orthop Res 15:18–23

    PubMed  Article  CAS  Google Scholar 

  56. Mata S, Fortin PR, Fitzcharles MA, Starr MR, Joseph L, Watts CS, Gore B, Rosenberg E, Chhem RK, Esdaile JM (1997) A controlled study of diffuse idiopathic skeletal hyperostosis: clinical features and functional status. Medicine 76:104–117

    PubMed  Article  CAS  Google Scholar 

  57. Mimatsu K, Kishi S, Hashizume Y (1997) Experimental chronic compression on the spinal cord of the rabbit by ectopic bone formation in the ligamentum flavum with bone morphogenetic protein. Spinal Cord 35:740–746

    PubMed  Article  CAS  Google Scholar 

  58. Miyamoto S, Takaoka K, Yonenobu K, Ono K (1992) Ossification of the ligamentum flavum induced by bone morphogenetic protein: an experimental study in mice. J Bone Joint Surg Br 74:279–283

    PubMed  CAS  Google Scholar 

  59. Moon SH, Park SR, Kim H, Kwon UH, Kim KH, Kim HS, Lee HM (2004) Biologic modification of ligamentum flavum cells by marker gene transfer and recombinant human bone morphogenetic protein-2. Spine 29:960–965

    PubMed  Article  Google Scholar 

  60. Morisu M (1994) Influence of foods on the posterior longitudinal ligament of the cervical spine and serum sex hormones. J Jpn Orthop Assoc 68:1056–1067 (in Japanese)

    Google Scholar 

  61. Murakami H (1988) Experimental study on ossification of spinal ligaments in the rabbit under influence of bone morphogenetic protein. J Jpn Orthop Assoc 62:1211–1220 (in Japanese)

    Google Scholar 

  62. Nagasawa H, Takahashi S, Kobayashi A, Tazawa H, Tashima Y, Sato K (2005) Effect of retinoic acid on murine preosteoblastic MC3T3-E1 cells. J Nutr Sci Vitaminol 51:311–318

    PubMed  CAS  Google Scholar 

  63. Nakase T, Ariga K, Yonenobu K, Tsumaki N, Luyten FP, Mukai Y, Sato I, Yoshikawa H (2001) Activation and localization of cartilage-derived morphogenetic protein-1 at the site of ossification of the ligamentum flavum. Eur Spine J 10:289–294

    PubMed  Article  CAS  Google Scholar 

  64. Numasawa T, Koga H, Ueyama K, Maeda S, Sakou T, Harata S, Leppert M, Inoue I (1999) Human retinoic X receptor β: complete genomic sequence and mutation search for ossification of posterior longitudinal ligament of the spine. J Bone Miner Res 14:500–508

    PubMed  Article  CAS  Google Scholar 

  65. Ogata N, Koshizuka Y, Miura T, Iwasaki M, Hosoi T, Shiraki M, Seichi A, Nakamura K, Kawaguchi H (2002) Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity. Spine 27:1765–1771

    PubMed  Article  Google Scholar 

  66. Ohtsuka K, Yanagihara M (1987) Epidemiological study of ossification of the spinal ligaments. Orthop MOOK 50:12–25 (in Japanese)

    Google Scholar 

  67. Okada Y, Motegi M, Fujita L, Furufu T, Yuji M, Tabe S (1987) Association of ossification of the spinal ligaments and sex hormones. Orthop MOOK 50:152–163 (in Japanese)

    Google Scholar 

  68. Okano T, Ishidou Y, Kato M, Imamura T, Yonemori K, Origuchi N, Matsunaga S, Yoshida H, ten Dijke P, Sakou T (1997) Orthotopic ossification of the spinal ligaments of Zucker fatty rats: a possible animal model for ossification of the human posterior longitudinal ligament. J Orthop Res 15:820–829

    PubMed  Article  CAS  Google Scholar 

  69. Okazaki T, Takuwa Y, Yamamoto M, Matsumoto T, Igarashi T, Kurokawa T, Ogata E (1984) Ossification of the paravertebral ligaments: a frequent complication of hypoparathyroidism. Metabolism 33:710–713

    PubMed  Article  CAS  Google Scholar 

  70. Ono K, Yonenobu K, Miyamoto S, Okada K (1999) Pathology of ossification of the posterior longitudinal ligament and ligamentum flavum. Clin Orthop 359:18–26

    PubMed  Article  Google Scholar 

  71. Park JB, Chang H, Lee JK (2001) Quantitative analysis of transforming growth factor-β1 in ligamentum flavum of lumbar spinal stenosis and disc herniation. Spine 26:E492–E495

    PubMed  Article  CAS  Google Scholar 

  72. Pennes DR, Martel W, Ellis CN (1985) Retinoid-induced ossification of the posterior longitudinal ligament. Skeletal Radiol 14:191–193

    PubMed  Article  CAS  Google Scholar 

  73. Sakou T, Taketomi E, Matsunaga S, Yamaguchi M, Sonoda S, Yashiki S (1991) Genetic study of ossification of the posterior longitudinal ligament in the cervical spine with human leukocyte antigen haplotype. Spine 16:1249–1252

    PubMed  Article  CAS  Google Scholar 

  74. Scarpa R, De Brasi D, Pivonello R, Marzullo P, Manguso F, Sodano A, Oriente P, Lombardi G, Colao A (2004) Acromegalic axial arthropathy: a clinical case-control study. J Clin Endocrinol Metab 89:598–603

    PubMed  Article  CAS  Google Scholar 

  75. Schmidt CC, Georgescu HI, Kwoh CK, Blomstrom GL, Engle CP, Larkin LA, Evans CH, Woo SL (1995) Effect of growth factors on the proliferation of fibroblasts from the medial collateral and anterior cruciate ligaments. J Orthop Res 13:184–190

    PubMed  Article  CAS  Google Scholar 

  76. Seichi A, Hoshino Y, Ohnishi I, Kurokawa T (1992) The role of calcium metabolism abnormalities in the development of ossification of the posterior longitudinal ligament of the cervical spine. Spine 17(Suppl 3):S30–S32

    PubMed  CAS  Article  Google Scholar 

  77. Sencan D, Elden H, Nacitarhan V, Sencan M, Kaptanoglu E (2005) The prevalence of diffuse idiopathic skeletal hyperostosis in patients with diabetes mellitus. Rheumatol Int 25:518–521

    PubMed  Article  CAS  Google Scholar 

  78. Shiigi E, Sugiyama T, Tanaka H, Murata H, Shirakura Y, Kawai S (2001) Possible involvement of vitamin D receptor gene polymorphism in male patients with ossification of spinal ligaments. J Bone Miner Metab 19:308–311

    PubMed  Article  CAS  Google Scholar 

  79. Shingyouchi Y, Nagahama A, Niida M (1996) Ligamentous ossification of the cervical spine in the late middle-aged Japanese men. Its relation to body mass index and glucose metabolism. Spine 21:2474–2478

    PubMed  Article  CAS  Google Scholar 

  80. Shirakura Y, Sugiyama T, Tanaka H, Taguchi T, Kawai S (2000) Hyperleptinemia in female patients with ossification of spinal ligaments. Biochem Biophys Res Commun 267:752–755

    PubMed  Article  CAS  Google Scholar 

  81. Soehle M, Casey AT (2002) Cervical spinal cord compression attributable to a calcified intervertebral disc in a patient with X-linked hypophosphatemic rickets: case report and review of the literature. Neurosurgery 51:239–242

    PubMed  Article  Google Scholar 

  82. Specchia N, Pagnotta A, Gigante A, Logroscino G, Toesca A (2001) Characterization of cultured human ligamentum flavum cells in lumbar spine stenosis. J Orthop Res 19:294–300

    PubMed  Article  CAS  Google Scholar 

  83. Tahara M, Aiba A, Yamazaki M, Ikeda Y, Goto S, Moriya H, Okawa A (2005) The extent of ossification of posterior longitudinal ligament of the spine associated with nucleotide pyrophosphatase gene and leptin receptor gene polymorphisms. Spine 30:877–880

    PubMed  Article  Google Scholar 

  84. Takuwa Y, Matsumoto T, Kurokawa T, Iizuka M, Hoshino Y, Hata K, Ogata E (1985) Calcium metabolism in paravertebral ligamentous ossification. Acta Endocrinol (Copenh) 109:428–432

    CAS  Google Scholar 

  85. Tanaka H, Nagai E, Murata H, Tsubone T, Shirakura Y, Sugiyama T, Taguchi T, Kawai S (2001) Involvement of bone morphogenic protein-2 (BMP-2) in the pathological ossification process of the spinal ligament. Rheumatology 40:1163–1168

    PubMed  Article  CAS  Google Scholar 

  86. Tanno M, Furukawa KI, Ueyama K, Harata S, Motomura S (2003) Uniaxial cyclic stretch induces osteogenic differentiation and synthesis of bone morphogenetic proteins of spinal ligament cells derived from patients with ossification of the posterior longitudinal ligaments. Bone 33:475–484

    PubMed  Article  CAS  Google Scholar 

  87. Terayama K (1989) Genetic studies on ossification of the posterior longitudinal ligament of the spine. Spine 14:1184–1191

    PubMed  Article  CAS  Google Scholar 

  88. Tsukamoto N, Maeda T, Miura H, Jingushi S, Hosokawa A, Harimaya K, Higaki H, Kurata K, Iwamoto Y (2006) Repetitive tensile stress to rat caudal vertebrae inducing cartilage formation in the spinal ligaments: a possible role of mechanical stress in the development of ossification of the spinal ligaments. J Neurosurg Spine 5:234–242

    PubMed  Google Scholar 

  89. Velan GJ, Currier BL, Clarke BL, Yaszemski MJ (2001) Ossification of the posterior longitudinal ligament in vitamin D-resistant rickets: case report and review of the literature. Spine 26:590–593

    PubMed  Article  CAS  Google Scholar 

  90. Vezyroglou G, Mitropoulos A, Antoniadis C (1996) A metabolic syndrome in diffuse idiopathic skeletal hyperostosis: a controlled study. J Rheumatol 23:672–676

    PubMed  CAS  Google Scholar 

  91. Vukicevic S, Latin V, Chen P, Batorsky R, Reddi AH, Sampath TK (1994) Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affinity binding to basement membranes. Biochem Biophys Res Commun 198:693–700

    PubMed  Article  CAS  Google Scholar 

  92. Wada A (1995) Affinity of estrogen binding in the cultured spinal ligament cells: an in vitro study using cells from spinal ligament ossification patients. J Jpn Orthop Assoc 69:440–449 (in Japanese)

    Google Scholar 

  93. Yamaguchi M (1991) Genetic study on OPLL in the cervical spine with HLA haplotype. J Jpn Orthop Assoc 65:527–535 (in Japanese)

    Google Scholar 

  94. Yamamoto Y, Furukawa K, Ueyama K, Nakanishi T, Takigawa M, Harata S (2002) Possible roles of CTGF/Hcs24 in the initiation and development of ossification of the posterior longitudinal ligament. Spine 27:1852–1857

    PubMed  Article  Google Scholar 

  95. Yamauchi T, Taketomi E, Matsunaga S, Sakou T (1999) Bone mineral density in patients with ossification of the posterior longitudinal ligament in the cervical spine. J Bone Miner Metab 17:296–300

    PubMed  Article  CAS  Google Scholar 

  96. Yevdokimova NY (2003) High glucose-induced alterations of extracellular matrix of human skin fibroblasts are not dependent on TSP-1-TGFβ1 pathway. J Diabetes Complications 17:355–364

    PubMed  Article  Google Scholar 

  97. Yonemori K, Imamura T, Ishidou Y, Okano T, Matsunaga S, Yoshida H, Kato M, Sampath TK, Miyazono K, ten Dijke P, Sakou T (1997) Bone morphogenetic protein receptors and activin receptors are highly expressed in ossified ligament tissues of patients with ossification of the posterior longitudinal ligament. Am J Pathol 150:1335–1347

    PubMed  CAS  Google Scholar 

  98. Yoshizawa T, Takizawa F, Iizawa F, Ishibashi O, Kawashima H, Matsuda A, Endo N, Kawashima H (2004) Homeobox protein MSX2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts. Mol Cell Biol 24:3460–3472

    PubMed  Article  CAS  Google Scholar 

  99. Yu WD, Panossian V, Hatch JD, Liu SH, Finerman GA (2001) Combined effects of estrogen and progesterone on the anterior cruciate ligament. Clin Orthop 383:268–281

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Orthopaedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai , 200092, China

    Hai Li, Lei-Sheng Jiang & Li-Yang Dai

Authors
  1. Hai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei-Sheng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Yang Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li-Yang Dai.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, H., Jiang, LS. & Dai, LY. Hormones and growth factors in the pathogenesis of spinal ligament ossification. Eur Spine J 16, 1075–1084 (2007). https://doi.org/10.1007/s00586-007-0356-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-007-0356-4

Keywords

  • Spine
  • Ligaments
  • Ossification
  • Hormones
  • Growth factors