MULTIDIMENSIONAL VALIDATION OF BONE CADENCE MODULATION IN OSTEOPOROTIC WOMEN: FROM CELLULAR TO COMPUTATIONAL APPROACHES

Abstract

Introduction: Fragility fracture, associated with osteoporosis due to low bone mass and poor bone architecture, are frequent in post-menopausal women. It becomes apparent that for an effective diagnosis and treatment of bone diseases, there is need to understand the molecular basis of bone remodeling. In this study, we propose to confirm some of the key diagnostic and therapeutic biomarkers which are involved in regulating Bone Cadence at multiple hierarchical levels ranging from cells to computer. The potential therapeutic targets of bone resorption, formation, and overall homeostasis were also investigated and better predictive models of fracture risk were also established through the assessment of biochemical and molecular markers in the panel. Materials and Methods: The study participant comprised of 500 osteoporotic women and 500 age matched apparently healthy women from Institute of molecular Biology and Biotechnology, the University of Lahore Pakistan. Women alliance involved candidates who had a T-score of ≤ -2.5 and did not have a record of bone related disease apart from osteoporosis and were postmenopausal. Biomarkers Sclerostin (SOST), Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL) and Osteoprotegerin (OPG) were measured in the collected samples by using enzyme linked immunosorbent assays (ELISA). Other analytes including collagen cross-links MMPs and miRNAs were also measured. Pearson’s coefficient of correlation and multiple correlation analysis, independent t test and ANOVA were performed to detect the correlation between biomarkers and the amount of spine and femur BMD. Results: As appeared for biomarkers, SOST, OPG, P1NP, and CTX-1 were significantly different between osteoporotic women and control. Interestingly, the concentration of RANKL was higher in osteoporotic women as compared to control group (48.59 ± 5.66 pg/mL) as well as DKK1 (8.54 ± 3.09 ng/mL). However, serum concentrations of P1NP, OPG, and ERα/ERβ were significantly decreased in osteoporotic women as compared to the controls. Analyzing the MicroRNAs (miR-21, miR-29b, miR-31) and Matrix Metalloproteinases (MMPs-9, MMPs-3), a remarkable change was observed challenge the facets of formally bone metabolism. A Negative correlation between the receptor for estrogen and osteoclastic activity which can be inferred from TRAP-5b and Collagen cross-link was identified and was found to be statistically significant. employing these biomarkers may be useful as markers of treatment effectiveness and as predictors of fracture chances. Conclusion: The present research work gives a multiple factorial approach to analyze modulation of bone cadence in osteoporotic women along with other molecular, physiological and biochemical markers involved in the bone remodeling process. Basically, the profile of the biomarkers is changed in osteoporosis; RANKL, SOST, and MMPs are increased, while OPG and ERβ are decreased, proving the idea of the crosstalk between bone remodeling and inflammation. The data give evidence of using these biomarkers for diagnosis and treatment and may help in planning individual patient treatment. This calculation along with biomarkers incorporated in the computational models can therefore transform fracture risk assessment of osteoporotic women.