Roles of Non-Canonical Wnt Signalling Pathways in Bone Biology

The Wnt signalling pathway is one of the central signalling pathways in bone development, homeostasis and regulation of bone mineral density. It consists of numerous Wnt ligands, receptors and co-receptors, which ensure tight spatiotemporal regulation of Wnt signalling pathway activity and thus tight regulation of bone tissue homeostasis. This enables maintenance of optimal mineral density, tissue healing and adaptation to changes in bone loading. While the role of the canonical/β-catenin Wnt signalling pathway in bone homeostasis is relatively well researched, Wnt ligands can also activate several non-canonical, β-catenin independent signalling pathways with important effects on bone tissue. In this review, we will provide a thorough overview of the current knowledge on different non-canonical Wnt signalling pathways involved in bone biology, focusing especially on the pathways that affect bone cell differentiation, maturation and function, processes involved in bone tissue structure regulation. We will describe the role of the two most known non-canonical pathways (Wnt/planar cell polarity pathways and Wnt/Ca2+ pathway), as well as other signalling pathways with a strong role in bone biology that communicate with the Wnt signalling pathway through non-canonical Wnt signalling. Our goal is to bring additional attention to these still not well researched but important pathways in the regulation of bone biology in the hope of prompting additional research in the area of non-canonical Wnt signalling pathways.

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09-P019 The role of the non-canonical Wnt signalling pathway in branching morphogenesis

Mechanisms of Development ◽

10.1016/j.mod.2009.06.349 ◽

2009 ◽

Vol 126 ◽

pp. S156

Author(s):

Laura L. Yates ◽

Carsten Schnatwinkel ◽

Jennifer N. Murdoch ◽

Debora Bogani ◽

Caroline J. Formstone ◽

...

Keyword(s):

Branching Morphogenesis ◽

Wnt Signalling ◽

Signalling Pathway ◽

Wnt Signalling Pathway ◽

Canonical Wnt

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Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish

10.1101/2020.05.20.106328 ◽

2020 ◽

Author(s):

Lucy M. McGowan ◽

Erika Kague ◽

Alistair Vorster ◽

Elis Newham ◽

Stephen Cross ◽

...

Keyword(s):

Bone Repair ◽

Bone Matrix ◽

Wnt Signalling ◽

Signalling Pathway ◽

Bone Homeostasis ◽

Mineral Density ◽

Matrix Deposition ◽

Wnt Signalling Pathway ◽

Canonical Wnt

SummaryBone homeostasis is a dynamic, multicellular process which is required throughout life to maintain bone integrity, prevent fracture and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in humans, as well as functional haematopoiesis of leukocytes in vivo, but the mechanisms by which it promotes bone health and repair are not fully understood. We used CRISPR-Cas9 to generate mutant zebrafish lacking Wnt16 (wnt16-/-) to study its effect on bone dynamically. wnt16 mutants displayed variable tissue mineral density and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16-/- and wild type (WT) zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell-dynamics in vivo. wnt16 mutants repaired fractures more slowly compared to WT zebrafish. Osteoblast cell number was reduced at the fracture site 4 days post-injury in wnt16 mutants, coinciding with prolonged activation of the canonical Wnt signalling pathway. Surprisingly, we found no evidence that the recruitment of innate immune cells to fractures was altered in wnt16 mutants. This study highlights zebrafish as an emerging model for functionally validating osteoporosis-associated genes and investigating fracture repair dynamically in vivo. Using this model, we demonstrate that Wnt16 protects against fracture and is likely to support bone repair by attenuating the activation of the canonical Wnt signalling pathway to facilitate osteoblast recruitment and bone matrix deposition.

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Glucose induces an autocrine activation of the Wnt/β-catenin pathway in macrophage cell lines

Biochemical Journal ◽

10.1042/bj20081426 ◽

2008 ◽

Vol 416 (2) ◽

pp. 211-218 ◽

Cited By ~ 55

Author(s):

Sasha H. Anagnostou ◽

Peter R. Shepherd

Keyword(s):

Cell Lines ◽

Nuclear Translocation ◽

Wnt Signalling ◽

Signalling Pathway ◽

Macrophage Cell ◽

Glucose Levels ◽

Wnt Signalling Pathway ◽

Hexosamine Pathway ◽

Number Of Genes ◽

Canonical Wnt

The canonical Wnt signalling pathway acts by slowing the rate of ubiquitin-mediated β-catenin degradation. This results in the accumulation and subsequent nuclear translocation of β-catenin, which induces the expression of a number of genes involved in growth, differentiation and metabolism. The mechanisms regulating the Wnt signalling pathway in the physiological context is still not fully understood. In the present study we provide evidence that changes in glucose levels within the physiological range can acutely regulate the levels of β-catenin in two macrophage cell lines (J774.2 and RAW264.7 cells). In particular we find that glucose induces these effects by promoting an autocrine activation of Wnt signalling that is mediated by the hexosamine pathway and changes in N-linked glycosylation of proteins. These studies reveal that the Wnt/β-catenin system is a glucose-responsive signalling system and as such is likely to play a role in pathways involved in sensing changes in metabolic status.

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Targeting mediators of Wnt signalling pathways by GnRH in gonadotropes

Journal of Molecular Endocrinology ◽

10.1677/jme-09-0168 ◽

2010 ◽

Vol 44 (4) ◽

pp. 195-201 ◽

Cited By ~ 7

Author(s):

Samantha Gardner ◽

Emmanouil Stavrou ◽

Patricia E Rischitor ◽

Elena Faccenda ◽

Adam J Pawson

Keyword(s):

Signal Transduction ◽

Gnrh Receptor ◽

Wnt Signalling ◽

Signalling Pathway ◽

Signalling Pathways ◽

Signal Transduction Pathways ◽

Cellular Processes ◽

Key Players ◽

Canonical Wnt ◽

Recent Demonstration

The binding of GnRH to its receptor on pituitary gonadotropes leads to the targeting of a diverse array of signalling mediators. These mediators drive multiple signal transduction pathways, which in turn regulate a variety of cellular processes, including the biosynthesis and secretion of the gonadotropins LH and FSH. Advances in our understanding of the mechanisms and signalling pathways that are recruited to regulate gonadotrope function are continually being made. This review will focus on the recent demonstration that key mediators of the canonical Wnt signalling pathway are targeted by GnRH in gonadotropes, and that these may play essential roles in regulating the expression of many of the key players in gonadotrope biology, including the GnRH receptor and the gonadotropins.

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