Scoliosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Overview

The exact pathogenesis of scoliosis is not fully understood. It is thought that scoliosis is the result of nutritional, endocrine, or genetic factors.The observation that curve development and progression correlate with the period of rapid adolescent growth appears to support a biomechanical contribution. However, multiple theories exist that attempt to explain the process by which the development takes place, and while each makes sense from a biomechanical standpoint. Malfunctioning melatonin and calmodulin signal pathway have been proposed for development of idiopathic scoliosis. In addition, theories suggesting a relative anterior spinal overgrowth (RASO) or an uncoupled neuro-osseus growth as a cause of idiopathic scoliosis. Skeletal immaturity is the major risk factor for the curve progression. It has been noted that girls with adolescent IS are taller and have a higher growth velocity during puberty in comparison to healthy individuals. A lower bone mineral density, leptin, cartilage oligomeric matrix protein and a high levels of growth hormone have seen to be influencing development of the disease. The effect of genetics on idiopathic scoliosis is well established. From the genetic standpoint, scoliosis is not easily explained by existing inheritance models. It has been recently seen the disease to be associated with loci on OS1, OS2, OS3, OS4, OS5, CHD7 and PAX1 gene.

Pathophysiology

  • Idiopathic scoliosis(IS) is the most common form of spinal deformity seen in healthy children and adoloscent during growth.
  • The pathophysiology of scoliosis in not clearly understood.
  • Many hypothesis have been postulated.

Role of Melatonin and Calmodulin

  • Animal studies have shown that pinealectomies lead to development of scoliosis due to lack of melatonin.[1][2][3]
  • Dysfunctional melatonin signal pathway involving MT2 receptors affecting osteoblast have been recommended.[4][5]
  • Calmodulin, a calcium-binding receptor protein, controls contraction in platelets and muscles, and interacts with melatonin. Increased levels of calmodulin in platelets and a disproportionate distribution of calmodulin in paraspinal muscles have been suggested in IS patients.[6][7][8]

Biomechanical Derangement

  • In literature, it has been shown that bone growth in the period of skeletal immaturity is retarded by mechanical compression on the growth plate and accelerated by growth plate tension.[9]
  • Because of the physiologic curvature in the normal thoracic spine, compressive force is delivered on the ventrally located part of the vertebral column, whereas distractive force is delivered on the dorsally located part.
  • This process leads to abnormal spinal curvature which is thought to be initiated by the rotation of vertebral bodies in the axial plane, which causes discrepant axial loading between the ventrally and dorsally located portions of the involved vertebrae.
  • Over time, the discrepancy manifests as a change in the directionality of spinal curvature; that is, the ventrally located part of the vertebral column becomes the concave side and the dorsally located part becomes the convex side of a lateral curve.
  • On MRI scans of IS patients, it seen that the length of the spinal cord is shorter in relation to the vertebral column and there is an increased prevalence of cerebellar tonsillar ectopia as well as an uncoordinated growth of the vertebral bodies in relation to the dorsal elements.[10][11][12]
  • This has led to theories proposing a relative anterior spinal overgrowth (RASO) or an uncoupled neuro-osseus growth as a cause of IS.[13]
  • The risk of curve progression in IS is related to skeletal immaturity.
  • It has also been shown that girls with adolescent IS are taller and have a higher growth velocity during puberty in comparison to healthy individuals.[14][15][16]

Role of Bone Mineral Density, Growth and Sex Hormones

  • Bone mineral density, growth, and sex hormones have been studied in the pathogenesis of IS.
  • Adolescent girls with IS have lower bone mineral density and a higher bone turnover rate.[17][18]
  • In addition, a decreased level of cartilage oligomeric matrix protein (COMP) in serum is seen in IS patients.[19]
  • A raised levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been associated with IS.[20][21]

Role of Leptin

  • A lower circulating levels of leptin, the “satiety” hormone have been suggested in pathogenesis of IS.[22][23][24]
  • Leptin is primarily secreted by adipocytes, and leptin receptor can be detected in chondrocytes and osteoblasts.
  • Leptin regulates the osteogenic differentiation of bone marrow stem cells and the function of chondrocytes by directly binding to leptin receptors.
  • Leptin functions to promotes chondrocyte proliferation and differentiation; regulates chondrocyte function by enhancing the production of collagen, matrix metalloproteinase (MMP), and bone morphogenetic protein (BMP) and remodels the cytoskeleton.

Genetics

  • The recognition of genetic influences in IS is well-documented.[25][26]
  • The general consensus is that, while families with dominant inheritance may exist, IS is generally a complex genetic disease that is not easily explained by existing inheritance models.[27]
  • A higher concordance seen in monozygotic (MZ) compared to dizygotic (DZ) twins.[28]
  • Polymorphisms in the collagen genes COL1A1, COL1A2, the fibrillin 1 gene FBN1, and the elastin gene ELN have been tested in family collections, but the results did not reveal evidence of linkage.[29][30]
  • Studies have shown five IS loci, OS1 (chr19p13.3), OS2 (chr 17p11), OS3 (chr 8q12.1-12.2), OS4 (chr 9q31-q34) and OS5 (chr 17q25-qter).[31]
  • Common single-nucleotide polymorphisms (SNPs) for gene within OS3, CHD7 have been associated with IS.[32][33][34][35]
  • Recently, a new IS susceptibility locus in an ~100-kb region of chromosome 20p11.22 downstream of PAX1 has been identified by Texas Scottish Rite Hospital for Children.[36]

Associated conditions

Scoliosis is sometimes associated with other conditions such as

However, the majority of people with adolescent scoliosis have no pain or other abnormalities.

Gross Pathology

There are no gross pathology findings associated with scoliosis.

Microscopic Pathology

  • On microscopic histopathological analysis,cells of convex side of deformation are chondroblasts. Cells isolated from the growth plates of the concave side of the deformation showed numerous features of neuro- and glioblasts. These cells form synapses, contain neurofilaments, and expressed neural and glial proteins.[37]

References

  1. ↑ THILLARD MJ (1959). "[Vertebral column deformities following epiphysectomy in the chick]". C R Hebd Seances Acad Sci. 248 (8): 1238–40. PMID 13629950.
  2. ↑ Machida M, Murai I, Miyashita Y, Dubousset J, Yamada T, Kimura J (1999). "Pathogenesis of idiopathic scoliosis. Experimental study in rats". Spine (Phila Pa 1976). 24 (19): 1985–9. PMID 10528372.
  3. ↑ Machida M, Dubousset J, Imamura Y, Iwaya T, Yamada T, Kimura J (1995). "Role of melatonin deficiency in the development of scoliosis in pinealectomised chickens". J Bone Joint Surg Br. 77 (1): 134–8. PMID 7822371.
  4. ↑ Moreau A, Wang DS, Forget S, Azeddine B, Angeloni D, Fraschini F; et al. (2004). "Melatonin signaling dysfunction in adolescent idiopathic scoliosis". Spine (Phila Pa 1976). 29 (16): 1772–81. PMID 15303021.
  5. ↑ Wang WW, Man GC, Wong JH, Ng TB, Lee KM, Ng BK; et al. (2014). "Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis". Int J Mol Sci. 15 (9): 17100–14. doi:10.3390/ijms150917100. PMC 4200781. PMID 25257530.
  6. ↑ Wu JZ, Wu WH, He LJ, Ke QF, Huang L, Dai ZS; et al. (2016). "Effect of Melatonin and Calmodulin in an Idiopathic Scoliosis Model". Biomed Res Int. 2016: 8460291. doi:10.1155/2016/8460291. PMC 5155075. PMID 28042574.
  7. ↑ Lowe T, Lawellin D, Smith D, Price C, Haher T, Merola A; et al. (2002). "Platelet calmodulin levels in adolescent idiopathic scoliosis: do the levels correlate with curve progression and severity?". Spine (Phila Pa 1976). 27 (7): 768–75. PMID 11923672.
  8. ↑ Acaroglu E, Akel I, Alanay A, Yazici M, Marcucio R (2009). "Comparison of the melatonin and calmodulin in paravertebral muscle and platelets of patients with or without adolescent idiopathic scoliosis". Spine (Phila Pa 1976). 34 (18): E659–63. doi:10.1097/BRS.0b013e3181a3c7a2. PMID 19680092.
  9. ↑ Stokes IA (2002). "Mechanical effects on skeletal growth". J Musculoskelet Neuronal Interact. 2 (3): 277–80. PMID 15758453.
  10. ↑ Chu WC, Lam WW, Chan YL, Ng BK, Lam TP, Lee KM; et al. (2006). "Relative shortening and functional tethering of spinal cord in adolescent idiopathic scoliosis?: study with multiplanar reformat magnetic resonance imaging and somatosensory evoked potential". Spine (Phila Pa 1976). 31 (1): E19–25. PMID 16395162.
  11. ↑ Abul-Kasim K, Overgaard A, Karlsson MK, Ohlin A (2009). "Tonsillar ectopia in idiopathic scoliosis: does it play a role in the pathogenesis and prognosis or is it only an incidental finding?". Scoliosis. 4: 25. doi:10.1186/1748-7161-4-25. PMC 2780387. PMID 19909551.
  12. ↑ Guo X, Chau WW, Chan YL, Cheng JC (2003). "Relative anterior spinal overgrowth in adolescent idiopathic scoliosis. Results of disproportionate endochondral-membranous bone growth". J Bone Joint Surg Br. 85 (7): 1026–31. PMID 14516040.
  13. ↑ Chu WC, Lam WM, Ng BK, Tze-Ping L, Lee KM, Guo X; et al. (2008). "Relative shortening and functional tethering of spinal cord in adolescent scoliosis - Result of asynchronous neuro-osseous growth, summary of an electronic focus group debate of the IBSE". Scoliosis. 3: 8. doi:10.1186/1748-7161-3-8. PMC 2474583. PMID 18588673.
  14. ↑ Normelli H, Sevastik J, Ljung G, Aaro S, Jönsson-Söderström AM (1985). "Anthropometric data relating to normal and scoliotic Scandinavian girls". Spine (Phila Pa 1976). 10 (2): 123–6. PMID 4002036.
  15. ↑ Willner S (1974). "A study of growth in girls with adolescent idiopathic structural scoliosis". Clin Orthop Relat Res (101): 129–35. PMID 4837925.
  16. ↑ Chazono M, Soshi S, Kida Y, Hashimoto K, Inoue T, Nakamura Y; et al. (2012). "Height velocity curves in female patients with idiopathic scoliosis". Stud Health Technol Inform. 176: 202–5. PMID 22744490.
  17. ↑ Hung VW, Qin L, Cheung CS, Lam TP, Ng BK, Tse YK; et al. (2005). "Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis". J Bone Joint Surg Am. 87 (12): 2709–16. doi:10.2106/JBJS.D.02782. PMID 16322621.
  18. ↑ Cheung CS, Lee WT, Tse YK, Lee KM, Guo X, Qin L; et al. (2006). "Generalized osteopenia in adolescent idiopathic scoliosis--association with abnormal pubertal growth, bone turnover, and calcium intake?". Spine (Phila Pa 1976). 31 (3): 330–8. doi:10.1097/01.brs.0000197410.92525.10. PMID 16449907.
  19. ↑ Gerdhem P, Topalis C, Grauers A, Stubendorff J, Ohlin A, Karlsson KM (2015). "Serum level of cartilage oligomeric matrix protein is lower in children with idiopathic scoliosis than in non-scoliotic controls". Eur Spine J. 24 (2): 256–61. doi:10.1007/s00586-014-3691-2. PMID 25427671.
  20. ↑ Sanders JO, Browne RH, Cooney TE, Finegold DN, McConnell SJ, Margraf SA (2006). "Correlates of the peak height velocity in girls with idiopathic scoliosis". Spine (Phila Pa 1976). 31 (20): 2289–95. doi:10.1097/01.brs.0000236844.41595.26. PMID 16985455.
  21. ↑ Willner S, Johnell O (1981). "Study of biochemical and hormonal data in idiopathic scoliosis in girls". Arch Orthop Trauma Surg. 98 (4): 251–5. PMID 6170273.
  22. ↑ Qiu Y, Sun X, Qiu X, Li W, Zhu Z, Zhu F; et al. (2007). "Decreased circulating leptin level and its association with body and bone mass in girls with adolescent idiopathic scoliosis". Spine (Phila Pa 1976). 32 (24): 2703–10. doi:10.1097/BRS.0b013e31815a59e5. PMID 18007248.
  23. ↑ Wang YJ, Yu HG, Zhou ZH, Guo Q, Wang LJ, Zhang HQ (2016). "Leptin Receptor Metabolism Disorder in Primary Chondrocytes from Adolescent Idiopathic Scoliosis Girls". Int J Mol Sci. 17 (7). doi:10.3390/ijms17071160. PMC 4964532. PMID 27447624.
  24. ↑ Burwell RG, Dangerfield PH, Moulton A, Anderson SI (2008). "Etiologic theories of idiopathic scoliosis: autonomic nervous system and the leptin-sympathetic nervous system concept for the pathogenesis of adolescent idiopathic scoliosis". Stud Health Technol Inform. 140: 197–207. PMID 18810025.
  25. ↑ Garland HG (1934). "HEREDITARY SCOLIOSIS". Br Med J. 1 (3816): 328. PMC 2444298. PMID 20778092.
  26. ↑ Wynne-Davies R (1975). "Infantile idiopathic scoliosis. Causative factors, particularly in the first six months of life". J Bone Joint Surg Br. 57 (2): 138–41. PMID 1141279.
  27. ↑ Wise CA, Gao X, Shoemaker S, Gordon D, Herring JA (2008). "Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood". Curr Genomics. 9 (1): 51–9. doi:10.2174/138920208783884874. PMC 2674301. PMID 19424484.
  28. ↑ Kesling KL, Reinker KA (1997). "Scoliosis in twins. A meta-analysis of the literature and report of six cases". Spine (Phila Pa 1976). 22 (17): 2009–14, discussion 2015. PMID 9306532.
  29. ↑ Carr AJ, Ogilvie DJ, Wordsworth BP, Priestly LM, Smith R, Sykes B (1992). "Segregation of structural collagen genes in adolescent idiopathic scoliosis". Clin Orthop Relat Res (274): 305–10. PMID 1345899.
  30. ↑ Miller NH, Mims B, Child A, Milewicz DM, Sponseller P, Blanton SH (1996). "Genetic analysis of structural elastic fiber and collagen genes in familial adolescent idiopathic scoliosis". J Orthop Res. 14 (6): 994–9. doi:10.1002/jor.1100140621. PMID 8982144.
  31. ↑ Weinstein, Stuart (2005). Turek's orthopaedics : principles and their application. Philadelphia: Lippincott Williams & Wilkins. ISBN 978-0781742986.
  32. ↑ Chan V, Fong GC, Luk KD, Yip B, Lee MK, Wong MS; et al. (2002). "A genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3". Am J Hum Genet. 71 (2): 401–6. doi:10.1086/341607. PMC 379172. PMID 12094330.
  33. ↑ Salehi LB, Mangino M, De Serio S, De Cicco D, Capon F, Semprini S; et al. (2002). "Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11". Hum Genet. 111 (4–5): 401–4. doi:10.1007/s00439-002-0785-4. PMID 12384783.
  34. ↑ Ocaka L, Zhao C, Reed JA, Ebenezer ND, Brice G, Morley T; et al. (2008). "Assignment of two loci for autosomal dominant adolescent idiopathic scoliosis to chromosomes 9q31.2-q34.2 and 17q25.3-qtel". J Med Genet. 45 (2): 87–92. doi:10.1136/jmg.2007.051896. PMID 17932119.
  35. ↑ Gao X, Gordon D, Zhang D, Browne R, Helms C, Gillum J; et al. (2007). "CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis". Am J Hum Genet. 80 (5): 957–65. doi:10.1086/513571. PMC 1852746. PMID 17436250.
  36. ↑ Sharma S, Londono D, Eckalbar WL, Gao X, Zhang D, Mauldin K; et al. (2015). "A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females". Nat Commun. 6: 6452. doi:10.1038/ncomms7452. PMC 4365504. PMID 25784220.
  37. ↑ Zaydman AM, Strokova EL, Kiseleva EV, Suldina LA, Strunov AA, Shevchenko AI; et al. (2018). "A New Look at Etiological Factors of Idiopathic Scoliosis: Neural Crest Cells". Int J Med Sci. 15 (5): 436–446. doi:10.7150/ijms.22894. PMC 5859766. PMID 29559832.

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