Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

Rockel, Jason S.; Yu, Chunying; Whetstone, Heather; Craft, April M.; Reilly, Katherine; Ma, Henry; Tsushima, Hiroyuki; Puviindran, Vijitha; Al‐Jazrawe, Mushriq; Keller, Gordon; Alman, Benjamin A.

doi:10.1172/jci80205

Cited by 50 publications

(43 citation statements)

References 65 publications

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“…In mice, Wnt9a/Wnt14 is both necessary and sufficient to specify joint‐forming domains in the limb, and Ihh is required for limb and jaw joint development . Conversely, HH activation has been found to inhibit joint development through repression of WNT signaling and Fgf18 expression . Going forward, it will be important to discern the extent to which these pathways establish early gene expression domains that prefigure joints versus more directly controlling chondrocyte and other cell fate at the joint (e.g., as discussed below for BMP signaling).…”

Section: Positioning the Joint Domaincontrasting

confidence: 55%

“…Somewhat differently, loss of Foxc1 results in pronounced bony fusions of the upper and lower jaw, a condition known as syngnathia . In addition to EDN1, BMP, and FGF signaling, WNT and HH signaling also play important roles in establishing joint domains . In mice, Wnt9a/Wnt14 is both necessary and sufficient to specify joint‐forming domains in the limb, and Ihh is required for limb and jaw joint development .…”

Section: Positioning the Joint Domainmentioning

confidence: 99%

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Building and maintaining joints by exquisite local control of cell fate

Smeeton

Askary

Crump

2016

WIREs Developmental Biology

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We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an “interzone” region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints.

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Section: Positioning the Joint Domaincontrasting

confidence: 55%

Section: Positioning the Joint Domainmentioning

confidence: 99%

Building and maintaining joints by exquisite local control of cell fate

Smeeton

Askary

Crump

2016

WIREs Developmental Biology

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“…In mouse chondrocytes activation of hedgehog signaling selectively inhibited β-catenin-induced FGF18 expression. The selectivity was shown to be due to the Hh mediated induction of a dominant negative isoform of TCF7L2 (dnTCF7L2) in so called interzone progenitor cells [182]. Moreover, Wnt/β-catenin signaling can have repressive effects on SHh signaling in a number of cancer cells [183].…”

Section: Hypoxia Hifs and Hedgehog Signaling: Another Liaisonmentioning

confidence: 99%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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“…HH signalling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny and promoted the expression of catabolic enzymes associated with OA. Stabilization of β‐catenin by knockdown of TCF7L2 isoforms or treatment with FGF18 rescued HH signalling–induced Fgf18 down‐regulation in chondrocytes . It is reported that Dickkopf‐1 (DKK‐1) and cyclopaminemay work as a potent antagonist of HH signalling.…”

Section: Targeting Hedgehog In Oa Treatmentmentioning

confidence: 99%

Functional role of hedgehog pathway in osteoarthritis

Xiao

Deng

et al. 2019

Cell Biochemistry & Function

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The hedgehog signalling pathway is one of the key regulators of metazoan development, and it plays an important role in the regulation of a variety of developmental and physiological processes. But it is aberrantly activated in many human diseases, including osteoarthritis (OA). In this study, we have reviewed the association of hedgehog signalling pathway in the development and progression of OA and evaluated the efforts to target this pathway for the prevention of OA. Usually in OA, activation of hedgehog induces up-regulation of the expression of hypertrophic markers, including type X collagen, increases production of nitric oxide and prostaglandin E2, several matrix-degrading enzymes including matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs in human knee joint cartilage leading to cartilage degeneration, and thus contributes in OA. Targeting hedgehog signalling might be a viable strategy to prevent or treat OA. Chemical inhibitors of hedgehog signalling is promising, but they cause severe side effects. Knockdown of HH gene is not an option for OA treatment in humans because it is not possible to delete HH in larger animals. Efficient knockdown of HH achieved by local delivery of small interfering RNA in future studies utilizing large animal OA models might be a more efficient approach for the prevention of OA. However, it remains a major problem to develop one single scaffold due to the different physiological functions of cartilage and subchondral bones possess. More studies are necessary to identify selective inhibitors for efficiently targeting the hedgehog pathway in clinical conditions.

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Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

Cited by 50 publications

References 65 publications

Building and maintaining joints by exquisite local control of cell fate

Building and maintaining joints by exquisite local control of cell fate

Metabolic zonation of the liver: The oxygen gradient revisited

Functional role of hedgehog pathway in osteoarthritis

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