Speaker
Description
Introduction
Osteoporosis (OP) is one of the most common metabolic bone diseases, affecting over 200 million people worldwide. At the cellular level, OP occurs due to an imbalance between resorptive osteoclasts and bone-forming osteoblasts. There are several subtypes of OP, this research focuses on the treatment of post-menopausal osteoporosis.
Methods
The planning of an appropriate in silico analysis model was utilized for both developing a bone model and identifying potential drug targets. The methods involved applying known molecular processes related to bone development and targeting these pathways in osteoporosis. By analysing data from PubMed, KEGG and IPA programs, we aimed to identify targets involved in bone formation and outline different stages of osteoporosis to form the appropriate model systems.
Results
Based on the in silico analysis, bone remodelling and the creation of a viable bone environment suggest using naturally occurring cell types while allowing sufficient time (4D) for osteoblast progenitor cells to differentiate. After this initial phase, adding osteoclast progenitors along with the necessary factors in a direct co-culture could potentially mimic real-life conditions to bone formation. To develop an OP model from a healthy bone model, the identified pathways indicate that overactivating osteoclasts can be achieved through the addition of Receptor Activator of Nuclear Factor κB Ligand (RANKL), or by utilizing decoy molecules against RANKL inhibiting Osteoprotegerin (OPG). Both molecules are secreted by osteoblast, and are responsible for the regulation of osteoclast differentiation and activation, through RAF1 and MAP3K pathways.
Another common inducer for all OP types is the vitamin D deficiency receptor/retinoid X receptor (VDR/XRX) pathway, which activates cell differentiation and cell proliferation for osteoblasts and regulates cell growth, bone mineralization and calcium homeostasis leading to similar models of necrotic bones.
Discussion
The RANK/RANKL/OPG mechanism is fundamental to our in silico model, as it represents a crucial step leading to osteoclast activation. It's also essential to consider estrogen levels and the signaling pathways of Estrogen Receptor Signaling (ERS) and VDR/XRX. Changes in sex hormone levels—particularly estrogen and testosterone—significantly impact the complex process of bone remodeling through IL-1, IL-6, TNF-α, and OPG. These cytokines and hormones are closely associated with the prevalence of OP, especially among the elderly, with a more pronounced effect on older women. Although several potential drug targets and processes exist within the VDR/XRX, ERS, and RANK/RANKL/OPG systems, our in silico-based design can facilitate the development of appropriate model systems to test both known and novel drugs.
References
Bai, L. et al. (2024) “Engineering bone/cartilage organoids: strategy, progress, and application,” Bone Research. Springer Nature.
Bonucci, E. et al. (2014) “Osteoporosis—Bone Remodeling and Animal Models,” Toxicologic Pathology, 42(6), pp. 957–969.
Mirza, F. et al. (2015) “Secondary osteoporosis: Pathophysiology and management,” European Journal of Endocrinology. BioScientifica Ltd., pp. R131–R151.
Owen, R. et al. (2018) “In vitro models of bone remodelling and associated disorders,” Frontiers in Bioengineering and Biotechnology. Frontiers Media S.A.
Streicher, C. et al. (2017) “Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells,” Scientific Reports, 7(1).