Abnormal Bone Mineralization in Adolescent Idiopathic Scoliosis and its Relation with Plasma and Tissue Expression of Osteopontin

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine occurring most commonly in girls between ages 10-16 during the pubertal growth spurt. Despite its high prevalence and clinical impact, etiology of AIS remains largely unknown. Among the number of proposed hypothesis and observations on the etiopathogenesis of AIS, low bone mineral density (BMD) is one of the most reported factor (Cheng et al. 1999; Hung et al. 2005; Cheung et al. 2006; Hui et al. 2011). However, the underlying mechanism of low BMD in AIS has not been sufficiently studied scientifically and its link to the etiopathogenesis is still not clear. From a previous pilot study, our group has reported the histological features of reduced osteoblastic activity in bone biopsy specimens obtained from AIS subjects intraoperatively, thus providing the early evidence of abnormal bone mineral acquisition and mineralization (Cheng et al. 2001).;Osteopontin (OPN) has been recognized as one the major non-collagen extracellular matrix proteins in bone and plays an important role in bone mineralization. Recent report suggested that AIS patients have higher OPN level than normal controls (Moreau et al. 2009). It was hypothesized that the low BMD in AIS is associated with abnormal bone matrix mineralization which may be related to abnormal expression of OPN in the plasma and at tissue level.;In this series of studies, the first part aimed to investigate the differential cortical and trabecular bone mineral density of AIS Vs normal controls. The non-dominant proximal femur areal BMD (aBMD) (femoral neck, Ward's triangle and greater trochanter) of the subjects were measured with dual-energy x-ray absorptiometry (DXA). The volumetric bone mineral density (vBMD) in non-dominant distal radius was measured with peripheral quantitative computed tomography (pQCT) that allows accurate three dimensional assessment of the cortical and trabecular bone mineral density and other parameters of bone quality. AIS was found to have lower aBMDs, trabecular BMD (TBMD) and cortical BMD (CBMD) in different age groups and year since menarche (YSM) groups. Furthermore, the percentage difference of CBMD between AIS and controls was increased with age while a decreasing trend was observed in the TBMD.;The second part of the study investigated the bone mineralization and bone micro-architecture with micro-computed tomography (micro-CT) and histomorphometry study of bone biopsies obtained from AIS and normal controls. Three-dimensional structural parameters including material bone mineral density (mBMD) and bone architecture were evaluated by micro-CT. Bone histomorphometry was assessed by undecalcified sectioning with Goldner's trichrome staining. mBMD of trabecular bone in AIS was found to be significantly lower than the normal control while no difference could be demonstrated in BV/TV, Tb.N, Tb.Th and SMI measurement between the two groups. It was also shown that the percentage of low-mineralized bone in AIS was significantly higher than that in normal controls.;The third part aimed to study the plasma OPN level and its association with the BMD in AIS Vs normal controls. Plasma OPN level in AIS and age-matched controls was measured by ELISA. With multivariate regression analysis, the plasma OPN level was found to be negatively correlated with Age and YSM in both AIS and normal controls. In addition, the plasma OPN level in AIS was significantly higher and correlated with the low trabecular BMD.;The fourth part of the study investigated the OPN expression in bone tissues level and its association with histomorphometric bone mineralization and bone micro-architectural parameters in AIS Vs normal controls. OPN expression in bone biopsy was semi-quantified by immunohistochemistry. It was found that the bone tissue OPN level was significantly higher in AIS and also positively correlated with plasma OPN level. In addition, in this pilot study, we found the trend that OPN expression in trabecular bone was negatively associated with mBMD, and positively with the percentage of low-mineralized bone.;The present study showed that AIS had lower bone mineralization than normal controls. The low cortical and trabecular BMD found in AIS is likely to be resulting from abnormal regulation of bone mineralization. The association of OPN with abnormal BMD and bone mineralization further suggested that abnormal OPN level might play an important role in affecting the bone mineral acquisition in AIS. All of these findings strongly supported the hypothesis that the low BMD in AIS is associated with abnormal bone matrix mineralization which could be related to abnormal expression of OPN. This study provided important additional insight into the possible mechanism of lower bone mineral density that might be linked to the etiopathogenesis, development and progression of the spinal deformity in AIS.