Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis.

Autor: Abhishek Shah A; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India., Chand D; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Ahamad S; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India., Porwal K; Division of Endocrinology and Center for Research on Anabolic Skeletal Targets for Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India., Chourasia MK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Mohanan K; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Srivastava KR; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: kinshuk.srivastava@cdri.res.in., Chattopadhyay N; Division of Endocrinology and Center for Research on Anabolic Skeletal Targets for Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: n_chattopadhyay@cdri.res.in.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Oct 22; Vol. 230 (Pt 2), pp. 116587. Date of Electronic Publication: 2024 Oct 22.
DOI: 10.1016/j.bcp.2024.116587
Abstrakt: Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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