Abstract
Objective. Despite the current revolution in molecular medicine that has benefitted the treatment of certain diseases (Ross 2002), idiopathic scoliosis has resisted attempts to understand the molecular basis of its curve development. Lowe et al (2002) in a longitudinal study of 55 AIS patients concluded that platelet calmodulin levels correlate closely with curve progression and stabilization by bracing or spine fusion. They suggest that the platelet is a “minimuscle” with a protein contractile system (actin and myosin) similar to that of skeletal muscle. Using Lowe’s data we found that percentage platelet calmodulin change correlates significantly with percentage Cobb angle change (ANOVA, p=0.0003, n=54) that led us to suggest a platelet/skeletal hypothesis to account for their findings as part of a cascade concept for the pathogenesis of AIS.
Hypothesis. The human immature vertebral body is unusual among mammals in lacking epiphyses. This may explain why an axial load transmitted directly from the intervertebral disc deforms mature vertebral body end-plates as an axial inward bulge (Brinckmann et al 1983). In immature normal vertebral bodies vascular “lakes” (resembling bunches of grapes) have been found adjacent to the disc growth plates in subjects aged 9 to 13 years of age (Mineiro 1965). These “lakes” may provide a susceptibility to platelet activation from vascular stasis and shear stresses. In addition to their role in hemostasis platelets contain many growth factors including TGF-βs in α-granules that are secreted at a fracture site (Bolander 1992). TGF-βs are found in human neonatal rib growth plates (Horner et al 1998) but, like estrogen receptors, have not yet been sought in human intervertebral disc growth plates. We hypothesize that in the presence of a small scoliosis curve (from unknown causes ?spine, rib, muscle, or nervous system) platelets, as they circulate through vessels in eccentrically-loaded and deforming immature vertebral bodies particularly about the curve apex in the presence of a basic defect, are activated also by repeated axial inward bulges of disc growth plates causing mechanical micro-insults with endothelial cell desquamation and the formation of a calcium-cadmodulin complex. The latter is associated with platelet contraction (shape change) and the secretion from α-granules of various growth factors including angiogenic regulators (platelet release reaction, Hartwig 2003, Reed 2002, Rendu and Brohard-Bohn 2002). These growth factors abet the hormone-driven growth of the already mechanically-compromised disc growth plates and induce anterior spinal overgrowth and curve progression. The basic defect in AIS could be 1) a platelet, endothelial, or subendothelial anomaly, defect, or functional (?hormonal) disorder, and 2) one or more genetic polymorphisms that involve platelet receptors (Afshar-Kharghan and Bray 2002) and putative estrogen receptors in vertebral disc growth plates (Inoue et al 2002ab). The predilection of progressive AIS for girls may be related to the cyclical platelet functions in women associated with normal uterine function (Jones et al 1983, Pansini et al 1986, Tarantino et al 1994, Faraday et 1997). Curve laterality is determined by factors that initiate curve progression. Low plasma melatonin of progressive AIS may act both by a reduced antagonism to calmodulin (Lowe 2000, Dubousset and Machida 2001) and facilitating platelet aggregation with secretion of growth factors from α-granules.
Conclusions. The platelet/skeletal hypothesis for progressive AIS and the cascade concept suggests much new research. The hypothesis has genetic, diagnostic, prognostic and potential therapeutic implications. It raises questions about the possibility of changes in platelet calmodulin levels in other progressive and resolving deformities that occur in the immature and adult skeleton.
The abstracts were prepared by Mr Peter Millner. Correspondence should be addressed to Peter Millner, Consultant Spinal Surgeon, Orthopaedic Surgery, Chancellor Wing, Ward 28 Office Suite, St James’ University Hospital, Beckett Street, Leeds LS9 7TF.
