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

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  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.
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