Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.

Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.

Identification of QTL genes for BMD variation using both linkage and gene-based association approaches.

Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.

Reducing radiation exposure in early-onset scoliosis surgery patients: novel use of ultrasonography to measure lengthening in magnetically-controlled growing rods.

BACKGROUND CONTEXT: Magnetically-controlled growing rod (MCGR) technology has been reported for the treatment of early-onset scoliosis (EOS). Such technology allows for regular and frequent outpatient rod distractions without the need for additional surgery. However, pre- and postdistraction spine radiographs are required to verify the amount of lengthening. This increased exposure to ionizing radiation in developing children significantly increases their risk profile for radiation-induced cancer and noncancerous morbidity. PURPOSE: This study addressed the first and novel application and reliability of the use of ultrasonography, that has no ionizing radiation exposure, as an alternative to plain radiographs in the visualizing and confirming of rod distractions. STUDY DESIGN: A prospective study. PATIENT SAMPLE: Six EOS patients who underwent surgical treatment with MCGRs were prospectively recruited. OUTCOME MEASURES: Imaging measurements based on ultrasound and plain radiographs. METHODS: All patients were imaged via ultrasound, ease of rod identification was established, and the reliability and reproducibility of optimal reference point selection assessed blindly by three individuals. The clinical algorithm, using ultrasound, was subsequently implemented. Plain radiographs served as controls. RESULTS: Assessment of the rod's neck distance on ultrasound demonstrated a high degree of interrater reliability (a=0.99; p<.001). Intrarater reliability remained high on repeat measurements at different time intervals (a=1.00; p<.001). Satisfactory interrater reliability was noted when measuring the rod's neck (a=0.73; p=.010) and high reliability was noted in assessing the housing of the rod (a=0.85; p=.01) on plain radiographs. Under blinded conditions, 2 mm rod distraction measured on radiographs corresponded to 1.7 mm distraction on the ultrasound (standard deviation: 0.24 mm; p<.001). Subsequently, the clinical algorithm using ultrasound, instead of radiographs, has been successfully implemented. CONCLUSIONS: This is the first study to report the use of a novel technique using noninvasive, nonionizing ultrasound to reliably document rod distractions in EOS patients. A high level of inter- and intrarater reliabilities were noted. More importantly, the use of ultrasonography may result in fewer whole spine radiographs from being taken in patients who have had MCGRs implanted for EOS; thereby decreasing their exposure to ionizing radiation and the potential risk of future radiation-induced diseases.

A systematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: insights and future directions for regenerative therapeutics.

Intervertebral disc degeneration is associated with low-back pain. Mesenchymal stem cells (MSCs) have been used to "regenerate" the disc. The aim of this study was to perform a systematic review of comparative controlled studies that have assessed the safety and efficacy of using MSCs for disc regeneration. Literature databases were extensively searched. Trial design, subject-type, MSC sources, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was performed. Twenty-four animal studies were included with 20.8% of the studies reporting randomization of groups. Trials in humans fulfilling inclusion criteria were not noted. The studies represented 862 discs that were injected with MSCs and 1,603 discs as controls. All three types of MSCs (ie, bone marrow, synovial, and adipose tissues) showed successful inhibition of disc degeneration. Bone-marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments. A 2.7% overall complication rate was noted, whereby complications were noted only in rabbits. Overall, evidence suggested that MSCs increased disc space height in the majority of animal models. This is the first systematic review to assess the safety and efficacy of MSCs for the treatment of disc degeneration. Short-term MSC transplantation is safe and effective; however, additional, larger, and higher-quality studies are needed to assess the long-term safety and efficacy. Inconsistencies in methodological design and outcome parameters prevent any robust conclusions. Human-based clinical trials are needed. Recommendations are further made to improve efficacy, reduce potential complications, and standardize techniques for future studies.

Low handgrip strength is a predictor of osteoporotic fractures: cross-sectional and prospective evidence from the Hong Kong Osteoporosis Study.

Handgrip strength (HGS) is a potentially useful objective parameter to predict fracture since it is an indicator of general muscle strength and is associated with fragility and propensity to fall. Our objective was to examine the association of HGS with fracture, to evaluate the accuracy of HGS in predicting incident fracture, and to identify subjects at risk of fracture. We analyzed a cross-sectional cohort with 2,793 subjects (1,217 men and 1,576 women aged 50-101 years) and a subset of 1,702 subjects which were followed for a total of 4,855 person-years. The primary outcome measures were prevalent fractures and incident major fragility fractures. Each standard deviation (SD) reduction in HGS was associated with a 1.24-fold increased odds for major clinical fractures even after adjustment for other clinical factors. A similar result was obtained in the prospective cohort with each SD reduction in HGS being associated with a 1.57-fold increased hazard ratio of fracture even after adjustment for clinical factors. A combination of HGS and femoral neck bone mineral density (FN BMD) T-score values (combined T-score), together with other clinical factors, had a better predictive power of incident fractures than FN BMD or HGS T-score alone with clinical factors. In addition, combined T-score has better sensitivity and specificity in predicting incidence fractures than FN BMD alone. This study is the first study to compare the predictive ability of HGS and BMD. We showed that HGS is an independent risk factor for major clinical fractures. Compared with using FN BMD T-score of -2.5 alone, HGS alone has a comparable predictive power to BMD, and the combined T-score may be useful to identify extra subjects at risk of clinical fractures with improved specificity.