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ZM-306416 prevents ovariectomy-induced bone loss by promoting osteoblastogenesis and inhibiting osteoclastogenesis

ABSTRACT: Osteoporosis affects millions of people worldwide, and current medications like bisphosphonates and denosumab are not effective enough in reversing bone loss. Moreover, these treatments have drawbacks, including jaw osteonecrosis and skin eczema. Hence, there is an urgent need for new drugs to treat osteoporosis. Drug library screening was performed by alkaline phosphatase (ALP) staining in osteoblasts to identify potential candidates for osteoporosis. qPCR, Western blot, ALP staining, alizarin red staining, and TRAP staining were conducted to assess the impact of ZM-306416 (ZM) on osteoblast and osteoclast differentiation in vitro. Additionally, RNA sequencing and pathway analysis were carried out to explore molecular mechanisms. Micro-CT scan and immunostaining were used to determine bone phenotypes in vivo. Drug library screening demonstrated that ZM enhances ALP activity in osteoblasts, indicating its potential as a pro-osteogenic agent. ZM exerts dual effects by promoting osteoblast differentiation through the Wnt/β-catenin signaling pathway and simultaneously inhibiting osteoclast differentiation by the NF-κB and MAPK signaling pathways. In an OVX mouse model, ZM effectively prevents bone loss by stimulating osteoblast formation and inhibiting osteoclast development. Our study revealed that ZM has a dual anti-osteoporosis effect by promoting osteoblastogenesis and inhibiting osteoclastogenesis, mediated via activation of Wnt/β-catenin signaling and suppression of NF-κB/MAPK cascades. These findings suggest that ZM could be a promising therapeutic strategy for alleviating osteoporosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE307058 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:This a model from the article: Mathematical model predicts a critical role for osteoclast autocrine regulation in the control of bone remodeling. Komarova SV, Smith RJ, Dixon SJ, Sims SM, Wahl LM Bone2003 Aug;33(2):206-15 14499354, Abstract: Bone remodeling occurs asynchronously at multiple sites in the adult skeleton and involves resorption by osteoclasts, followed by formation of new bone by osteoblasts. Disruptions in bone remodeling contribute to the pathogenesis of disorderssuch as osteoporosis, osteoarthritis, and Paget's disease. Interactions among cells of osteoblast and osteoclast lineages are critical in the regulation of bone remodeling. We constructed a mathematical model of autocrine and paracrine interactions among osteoblasts and osteoclasts that allowed us to calculate cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Themodel predicted different modes of dynamic behavior: a single remodeling cycle in response to an external stimulus, a series of internally regulated cycles of bone remodeling, or unstable behavior similar to pathological bone remodeling in Paget's disease. Parametric analysis demonstrated that the mode of dynamic behaviorin the system depends strongly on the regulation of osteoclasts by autocrine factors, such as transforming growth factor beta. Moreover, simulations demonstratedthat nonlinear dynamics of the system may explain the differing effects of immunosuppressants on bone remodeling in vitro and in vivo. In conclusion, the mathematical model revealed that interactions among osteoblasts and osteoclasts result in complex, nonlinear system behavior, which cannot be deduced from studies of each cell type alone. The model will be useful in future studies assessing the impact of cytokines, growth factors, and potential therapies on the overall process ofremodeling in normal bone and in pathological conditions such as osteoporosis and Paget's disease. The model reproduces Fig 2A and Fig 2B of the paper. Note that the Y-axis scale is not right, the osteoblast steadystate is approximatley 212 and not 0 as depicted in the figure. Also, there is atypo in the equation for x2_bar which has been corrected here. Model successfully tested on MathSBML. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

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ZM-306416 prevents ovariectomy-induced bone loss by promoting osteoblastogenesis and inhibiting osteoclastogenesis

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