Wnt signaling in cartilage development and diseases: lessons from animal studies

Usami, Yu; Gunawardena, Aruni T; Iwamoto, Masahiro; Enomoto‐Iwamoto, Motomi

doi:10.1038/labinvest.2015.142

Cited by 169 publications

(147 citation statements)

References 99 publications

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“…TCF7L2 was also shown to be expressed in primary osteoarthritic ACCs and to potentiate the pro-catabolic and apoptotic actions of NFκB [40]. These findings match the ability of canonical WNT signaling to promote GP maturation and AC degeneration [41]. …”

Section: Beta-scaffold Transcription Factors With Minor Groove Conmentioning

confidence: 89%

Transcriptional control of chondrocyte specification and differentiation

Liu

Samsa

Zhou

et al. 2017

Seminars in Cell & Developmental Biology

135

112

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A milestone in the evolutionary emergence of vertebrates was the invention of cartilage, a tissue that has key roles in modeling, protecting and complementing the bony skeleton. Cartilage is elaborated and maintained by chondrocytes. These cells derive from multipotent skeletal progenitors and they perform highly specialized functions as they proceed through sequential lineage commitment and differentiation steps. They form cartilage primordia, the primary skeleton of the embryo. They then transform these primordia either into cartilage growth plates, temporary drivers of skeletal elongation and endochondral ossification, or into permanent tissues, namely articular cartilage. Chondrocyte fate decisions and differentiated activities are controlled by numerous extrinsic and intrinsic cues, and they are implemented at the gene expression level by transcription factors. The latter are the focus of this review. Meritorious efforts from many research groups have led over the last two decades to the identification of dozens of key chondrogenic transcription factors. These regulators belong to all types of transcription factor families. Some have master roles at one or several differentiation steps. They include SOX9 and RUNX2/3. Others decisively assist or antagonize the activities of these masters. They include TWIST1, SOX5/6, and MEF2C/D. Many more have tissue-patterning roles and regulate cell survival, proliferation and the pace of cell differentiation. They include, but are not limited to, homeodomain-containing proteins and growth factor signaling mediators. We here review current knowledge of all these factors, one superclass, class, and family at a time. We then compile all knowledge into transcriptional networks. We also identify remaining gaps in knowledge and directions for future research to fill these gaps and thereby provide novel insights into cartilage disease mechanisms and treatment options.

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Section: Beta-scaffold Transcription Factors With Minor Groove Conmentioning

confidence: 89%

Transcriptional control of chondrocyte specification and differentiation

Liu

Samsa

Zhou

et al. 2017

Seminars in Cell & Developmental Biology

135

112

View full text Add to dashboard Cite

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“…Proper control of the canonical Wnt signaling pathway is essential for maintaining cartilage homeostasis (25, 26). Numerous studies have reported upregulated canonical Wnt signaling in osteoarthritis (OA) and ankylosing spondylitis (14, 27), where it is thought that this pathway promotes chondrocyte hypertrophy and breakdown of adult cartilage (20).…”

Section: Sclerostin In Osteoarthritis and Rheumatic Joint Diseasementioning

confidence: 99%

Sclerostin expression and functions beyond the osteocyte

Weivoda

Youssef

Oursler

2017

Bone

103

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Sclerostin, the product of the SOST gene, is a secreted inhibitor of Wnt signaling that is produced by osteocytes to regulate bone formation. While it is often considered an osteocyte-specific protein, SOST expression has been reported in numerous other cell types, including hypertrophic chondrocytes and cementocytes. Of interest, SOST/sclerostin expression is altered in certain pathogenic conditions, including osteoarthritis and rheumatic joint disease, and it is unclear whether sclerostin plays a protective role or whether sclerostin may mediate disease pathogenesis. Therefore, as anti-sclerostin antibodies are being developed for the treatment of osteoporosis, it is important to understand the functions of sclerostin beyond the regulation of bone formation.

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“…Two of the best characterized non-canonical Wnt signaling pathways are the Wnt/Ca 2+ and Wnt/planar cell polarity (PCP) pathways which activate calmodulin-dependent kinase II (CaMKII) and c-Jun N-terminal kinase (JNK), respectively. Wnt signaling plays an important role in various developmental processes including cartilage and bone formation and increasing evidence suggests that aberrant Wnt signaling contributes to cartilage destruction in OA 10, 11 .…”

Section: Introductionmentioning

confidence: 99%

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Huang

Chubinskaya

Liao

et al. 2017

Osteoarthritis and Cartilage

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Objective Aberrant Wnt signaling may contribute to osteoarthritis (OA) but the Wnt family members involved have not been fully identified. The purpose of this study was to investigate the role of Wnt5a as a potential mediator of cartilage destruction in OA. Design Immunohistochemistry to detect Wnt5a was performed using normal and OA human articular cartilage. Cultured normal human chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus or recombinant Wnt5a protein with or without pretreatment using a panel of signaling inhibitors. Expression of Wnt5a, anabolic genes and catabolic genes were determined by quantitative real-time PCR. Production of Wnt5a protein and matrix metalloproteinases (MMPs) as well as activation of signaling proteins were analyzed by immunoblotting. Results Wnt5a was present in human articular cartilage with OA changes and its expression and secretion were increased in FN-f stimulated chondrocytes. FN-f stimulated Wnt5a production through the JNK and ERK pathways. Wnt5a reduced aggrecan gene expression after 48 hours of treatment. Wnt5a seemed to promote MMP1, -3, and -13 expression as well as MMP1 and MMP13 protein production in normal human chondrocytes. Wnt5a inhibitor peptides did not affect FN-f induced MMP production. Wnt5a activated β-catenin independent signaling including calmodulin-dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt. Inhibition of JNK, p38, ERK, PI-3 kinase and CaMKII by specific signaling inhibitors suppressed Wnt5a mediated MMP1 and MMP13 production. Conclusions Wnt5a is present in human OA cartilage and can promote chondrocyte catabolic activity through non-canonical Wnt signaling, which suggests a potential role in OA.

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Wnt signaling in cartilage development and diseases: lessons from animal studies

Cited by 169 publications

References 99 publications

Transcriptional control of chondrocyte specification and differentiation

Transcriptional control of chondrocyte specification and differentiation

Sclerostin expression and functions beyond the osteocyte

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

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