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Review
. 2020 Aug:137:115368.
doi: 10.1016/j.bone.2020.115368. Epub 2020 May 4.

Wnt signaling in chondroprogenitors during long bone development and growth

Takeshi Oichi  1 , Satoru Otsuru  1 , Yu Usami  2 , Motomi Enomoto-Iwamoto  1 , Masahiro Iwamoto  3
Affiliations
Review

Wnt signaling in chondroprogenitors during long bone development and growth

Takeshi Oichi et al. Bone. 2020 Aug.

Abstract

Wnt signaling together with other signaling pathways governs cartilage development and the growth plate function during long bone formation and growth. β-catenin-dependent Wnt signaling is a specific lineage determinant of skeletal mesenchymal cells toward chondrogenic or osteogenic direction. Once cartilage forms and the growth plate organize, Wnt signaling continues to regulate proliferation and differentiation of the growth plate chondrocytes. Although chondrocytes in the growth plate have a high capacity to proliferate, new cells must be supplied to the growth plate from chondroprogenitor population. Advances in in vivo cell tracking techniques have demonstrated the importance of Wnt signaling in driving tissue renewal. The Wnt-responsive cells, genetically marked by the Wnt-reporter system, are found as stem cells in various tissues. Similarly, Wnt-responsive cells are found in the periphery of the growth plate and expanded to constitute entire column structure, indicating that Wnt signaling participates in the regulation of chondroprogenitors in the growth plate. This review will discuss advancements in research of progenitors in the growth plate, specifically focusing on Wnt/β-catenin signaling.

Keywords: Chondroprogenitor; Growth plate; Wnt signaling.

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Figures

Fig.1
Fig.1. Canonical Wnt signaling.
In the absence of Wnt stimulation (left), cytoplasmic β-catenin protein are phosphorylated by protein kinases including GSK-3P (glycogen synthase kinase 3β) and CK1 (casein kinase 1), forming a destruction complex with GSK-3β, CK1, APC (adenomatous polyposis coli) and the scaffold protein Axin. The phosphorylated β-catenin is then ubiquitinated by β-TrCP (β-transducing repeat-containing protein) and recognized as a substrate for proteasome-dependent protein degradation, keeping the cytoplasmic and nuclear β-catenin amount low. In the presence of Wnt stimulation (right), Wnt ligands bind to Frizzled and LRP5/6 (low-density lipoprotein related receptor 5/6), activating downstream signaling. β-catenin is released from destruction complex and stabilized in cytoplasm. Cytoplasmic β-catenin then enters the nucleus and binds to TCF/LEF (T-cell factor/lymphoid enhancer factor), inducing transcription of the target genes.
Fig.2
Fig.2. Schematic diagram of the proposed Wnt-responsive cell contribution to postnatal growth plate formation.
Chondroprogenitors in the outermost layer of the growth plate (green) provide new chondrocytes (blue) contributing to the appositional growth. Ranvier’s groove Wnt-responsive cells (yellow) do not significantly contribute to the growth plate formation and can be controlled to prevent their chondrogenic differentiation by β-catenin signaling. These cells ectopically express chondrocyte phenotype (red) when lose β-catenin signaling. Wnt/β catenin signaling might also regulate chondroprogenitors (green) or their progenies (light green and blue) in the resting zone after secondary ossification center formation (interstitial growth).
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