Inhibition of β-catenin signaling causes defects in postnatal cartilage development

Chen, Mo; Zhu, Min; Awad, Hani A.; Li, Tian-Fang; Sheu, Tzong‐Jen; Boyce, Brendan F.; Chen, Di; O’Keefe, Regis J.

doi:10.1242/jcs.020362

Cited by 130 publications

(107 citation statements)

References 31 publications

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“…For example, mice conditionally deficient in beta-catenin die before birth 88 . However, transgenic mice expressing the inhibitor of beta-catenin and T cell factor (ICAT) driven by Col2a1 regulatory elements permit the post-natal investigation of beta-catenin downregulation in chondrocytes 89,90 . In these mice, the articular and growth plate chondrocytes show a delay of chondrocyte differentiation with smaller proliferating and hypertrophic zones in the growth plate, decreased chondrocyte proliferation, increased apoptosis, and decreased levels of MMP-13 (which is typically upregulated in OA).…”

Section: Developmental Signaling Pathways In Post Natal Chondrocytesmentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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Section: Developmental Signaling Pathways In Post Natal Chondrocytesmentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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“…Defects in chondrocyte biology also result in delayed formation of the secondary ossification center that is often observed in chondrodysplastic phenotypes (18)(19)(20). Indeed, the formation of the secondary ossification center in the epiphysis of the Shn2/3-DKO femurs was also delayed (Fig.…”

Section: Resultsmentioning

confidence: 83%

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3

Jones

Schweitzer

Wein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Formation and remodeling of the skeleton relies on precise temporal and spatial regulation of genes expressed in cartilage and bone cells. Debilitating diseases of the skeletal system occur when mutations arise that disrupt these intricate genetic regulatory programs. Here, we report that mice bearing parallel null mutations in the adapter proteins Schnurri2 (Shn2) and Schnurri3 (Shn3) exhibit defects in patterning of the axial skeleton during embryogenesis. Postnatally, these compound mutant mice develop a unique osteochondrodysplasia. The deletion of Shn2 and Shn3 impairs growth plate maturation during endochondral ossification but simultaneously results in massively elevated trabecular bone formation. Hence, growth plate maturation and bone formation can be uncoupled under certain circumstances. These unexpected findings demonstrate that both unique and redundant functions reside in the Schnurri protein family that are required for proper skeletal patterning and remodeling.chondrodysplasia | osteoblast | skeletogenesis

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“…However, TG mice misexpressing Dkk1 or Dkk2 in chondrocytes or hypertrophic chondrocytes showed normal development of cartilage and bone. Chen et al (10) found that inhibition of b-catenin activity by chondrocyte-specific overexpression of ICAT (inhibitor of b-catenin and TCF) in mice caused reduced chondrocyte proliferation and differentiation, delayed formation of the secondary ossification center, reduced angiogenesis, and resulted in small skeletal size. However, we found here that misexpression of Dkk1 in chondrocytes or hypertrophic chondrocytes does not cause such defects in TG mice.…”

Section: Discussionmentioning

confidence: 99%

“…(8,9) For instance, chondrocyte-specific inhibition of bcatenin causes defects in postnatal cartilage development. (10)Dkk modulates Wnt signaling by binding to Lrp5 and Lrp6 coreceptors of Wnt. (12) However, there is no direct evidence for a role of Dkk in the coupling of cartilage and bone development with angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte-and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. ß

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Inhibition of β-catenin signaling causes defects in postnatal cartilage development

Cited by 130 publications

References 31 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

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