Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation

Tiet, Tri Dung; Hopyan, Sevan; Nadesan, Puviindran; Gökgöz, Nalan; Poon, Raymond; Lin, Alvin; Yan, Taiqiang; Andrulis, Irene L.; Alman, Benjamin A.; Wunder, Jay S.

doi:10.2353/ajpath.2006.050001

Cited by 140 publications

(123 citation statements)

References 45 publications

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“…To circumvent this issue, mice with the same tamoxifen-induced expression of crerecombinase in chondrocytes were crossed with conditional beta-catenin floxed mice, resulting in stabilization of beta-catenin 91 107 . Similar to the dose and efficacy of cyclopamine, the small molecule N-…”

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

293

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

293

340

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“…Previous studies have shown that the hedgehog signaling pathway, a major regulator of the cell cycle and differentiation in chondrocytes (29), was constitutively active in primary chondrosarcomas (30). Since MATN3 is believed to intervene in hedgehog regulation of chondrogenesis (10,31), overexpression of hedgehog signaling and overexpression of MATN3 might be functionally linked.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

Vincourt¹,

Vignaud²,

Lionneton³

et al. 2008

Arthritis & Rheumatism

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Conclusion. Aberrant expression and processing of MATN3 are hallmarks of conventional cartilaginous neoplasms. A particular step in the maturation of MATN3 limits its processing through the secretion machinery, resulting in its intracellular accumulation upon increased expression. Soluble, secreted MATN3, however, down-regulates SOX9 at the messenger RNA and protein levels. The first EGF-like domain of MATN3 is a critical determinant of its regulatory activity toward SOX9. These activities of MATN3 suggest that its increased expression in osteoarthritis might contribute to the degeneration of articular cartilage.Articular cartilage is mostly made of extracellular specialized collagens and proteoglycans, with physical properties that support frictionless movements and the load-bearing capacity of the joints. Homeostasis of carti-

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“…The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

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

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Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.isocitrate dehydrogenase | cartilage tumor | hedgehog E nchondromas, one of the most common benign tumors occurring in bone, are present in more than 3% of the population (1, 2). They are composed of cells derived from chondrocytes and occur as solitary lesions or multiple lesions in enchondromatosis syndromes (Ollier disease or Maffucci syndrome-in the latter, enchondromas are associated with vascular malformations). Clinical problems caused by enchondromas include pain, fractures, and skeletal deformity. There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14). Disruption of this feedback loop can result in either skeletal dysplasias with abnormal bone growth or enchondromas; 5% of enchondromas harbor mutation in parathyroid hormone-like hormone receptor (PTHR1), resulting in activation of Hh signaling (6,(10)(11)(12)(13)(14), and expression of a mutant PTHR1 or overexpression of the Hh-regulated transcription factor Gli2 under the Col2a1 promoter causes enchondroma-like cartilage lesions to develop adjacent to the growth-plate ...

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Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation

Cited by 140 publications

References 45 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

Mutant IDH is sufficient to initiate enchondromatosis in mice

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