Objectives: The Wnt signaling pathway is a key pathway in various processes, including bone metabolism. In this review, current knowledge of all extracellular modulators of the canonical Wnt signaling in bone metabolism is summarized and discussed.
Methods: The PubMed database was searched using the following keywords: canonical Wnt signaling, β-catenin bone metabolism, BMD, osteoblast, osteoporosis, Wnt, LRPs, Frizzleds, sFRPs, sclerostin or SOST, dickkopfs, Wif1, R-spondins, glypicans, SOST-dc1 and kremen, all separately as well as in different combinations.
Results: Canonical Wnt signaling is considered to be one of the major pathways regulating bone formation. Consequently, a large number of studies were performed to elucidate the role of numerous proteins in canonical Wnt signaling and bone metabolism. These studies led to the identification of novel modulators of the pathway like the R-spondin and glypican protein families. Furthermore novel insights are gained in the regulatory role of the different Wnt proteins. Finally, due to its function in bone formation, the pathway is an interesting target for the development of therapeutics for osteoporosis and other bone diseases. In this review, we discuss the promising results of the Wnt modulators sclerostin, Dkk1 and sFRP1 as targets for osteoporosis treatment.
Conclusion: The increasing number of studies into the exact function of all proteins in the canonical Wnt pathway in general and in bone metabolism already led to novel insights in the regulation of the canonical Wnt pathway. In this review we covered the current knowledge of all extracellular modulators of canonical Wnt signaling.
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http://dx.doi.org/10.1016/j.semarthrit.2013.01.004 | DOI Listing |
Bone Res
January 2025
Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.
View Article and Find Full Text PDFBioorg Chem
January 2025
Department of Zoology, Aligarh Muslim University, Aligarh 202002, India. Electronic address:
Small molecules are emerging as potential candidates for treating osteoporosis by activating canonical Wnt signaling. These candidates work either by inhibiting DKK-1, sclerostin, SFRP-1, NOTUM, and S1P lyase or by preventing β-catenin degradation through inhibition of GSK-3β, or by targeting Dvl-CXXC5 and axin/β-catenin interactions. While many of these anti-osteoporotic small molecules are in preclinical development, the paucity of FDA-approved small molecules, or promising candidates, that have progressed to clinical trials for treating bone disorders through this mechanism poses a challenge.
View Article and Find Full Text PDFBiomolecules
January 2025
Division of Endocrinology Diabetes and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.
We previously reported that mediated the improvement in body composition in testosterone (T)-treated hypogonadal men by shifting adipogenesis to myogenesis. Previous preclinical studies suggest that regulates , an important osteoblastic transcription factor, expression and activity. However, the changes in , and other genes/proteins involved in osteoblastogenesis with T therapy in hypogonadal men are unexplored.
View Article and Find Full Text PDFNat Rev Mol Cell Biol
January 2025
Donnelly Centre for Cellular and Biomolecular Research and Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt-β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell-cell communication system.
View Article and Find Full Text PDFBiomimetics (Basel)
January 2025
Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA.
The surface topography and chemistry of titanium-aluminum-vanadium (Ti6Al4V) implants play critical roles in the osteoblast differentiation of human bone marrow stromal cells (MSCs) and the creation of an osteogenic microenvironment. To assess the effects of a microscale/nanoscale (MN) topography, this study compared the effects of MN-modified, anodized, and smooth Ti6Al4V surfaces on MSC response, and for the first time, directly contrasted MN-induced osteoblast differentiation with culture on tissue culture polystyrene (TCPS) in osteogenic medium (OM). Surface characterization revealed distinct differences in microroughness, composition, and topography among the Ti6Al4V substrates.
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