Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy

Mak, Kin Cheung; Kronenberg, Henry M.; Chuang, Pao-Tien; Mackem, Susan; Yang, Yingzi

doi:10.1242/dev.018044

Cited by 243 publications

(214 citation statements)

References 26 publications

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“…Interestingly, during OA, articular chondrocytes undergo phenotypic and gene expression changes that recapitulate normal growth plate chondrocyte development 6 . Moreover, Hh signaling is important in the post-natal maintenance of articular cartilage and trabecular bone 69,93,95 . I hypothesize that, during OA, Hh signaling is dysregulated in articular cartilage.…”

Section: Animal Models Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

285

332

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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: Animal Models Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

285

332

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“…In long bone development, it has been previously reported that BMP signaling in the cartilage may mediate the effect of Ihh (Mak et al, 2008) and that Ihh is a direct target of the BMP pathway (Retting et al, 2009). Given the established role of the BMP pathway during cranial suture formation (Warren et al, 2003), we decided to examine the possible relationship between Ihh and Bmp in the suture mesenchyme and calvarial bones.…”

Section: Loss Of Ihh In the Developing Calvaria Negatively Affects Bmmentioning

confidence: 99%

Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling

Lenton

James

Manu

et al. 2011

Genesis

102

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Summary: Much is known regarding the role of Indian hedgehog (Ihh) in endochondral ossification, where Ihh regulates multiple steps of chondrocyte differentiation. The Ihh 2/2 phenotype is most notable for severely foreshortened limbs and a complete absence of mature osteoblasts. A far less explored phenotype in the Ihh 2/2 mutant is found in the calvaria, where bones form predominately through intramembranous ossification. We investigated the role of Ihh in calvarial bone ossification, finding that proliferation was largely unaffected. Instead, our results indicate that Ihh is a pro-osteogenic factor that positively regulates intramembranous ossification. We confirmed through histologic and quantitative gene analysis that loss of Ihh results in reduction of cranial bone size and all markers of osteodifferentiation. Moreover, in vitro studies suggest that Ihh loss reduces Bmp expression within the calvaria, an observation that may underlie the Ihh 2/2 calvarial phenotype. In conjunction with the newly recognized roles of Hedgehog deregulation in craniosynostosis, our study defines Ihh as an important positive regulator of cranial bone ossification.

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“…These findings suggest that Ihh and PTHrP function in a negative feedback system during latestage chondrocyte development. Recently, it has also been shown that Ihh stimulates chondrocyte maturation and calcification in a PTHrP-independent manner (Kobayashi et al, 2005;Amano et al, 2008;Mak et al, 2008). These results indicate that the precise role of the PTHrP/Ihh negative feedback loop is more complicated than initially proposed and that the regulation of PTHrP expression is complex.…”

Section: Introductionmentioning

confidence: 96%

Sox9 Family Members Negatively Regulate Maturation and Calcification of Chondrocytes through Up-Regulation of Parathyroid Hormone–related Protein

Amano

Hata²,

Sugita³

et al. 2009

MBoC

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Sox9 is a transcription factor that plays an essential role in chondrogenesis and has been proposed to inhibit the late stages of endochondral ossification. However, the molecular mechanisms underlying the regulation of chondrocyte maturation and calcification by Sox9 remain unknown. In this study, we attempted to clarify roles of Sox9 in the late stages of chondrocyte differentiation. We found that overexpression of Sox9 alone or Sox9 together with Sox5 and Sox6 (Sox5/6/9) inhibited the maturation and calcification of murine primary chondrocytes and up-regulated parathyroid hormone-related protein (PTHrP) expression in primary chondrocytes and the mesenchymal cell line C3H10T1/2. Sox5/6/9 stimulated the early stages of chondrocyte proliferation and development. In contrast, Sox5/6/9 inhibited maturation and calcification of chondrocytes in organ culture. The inhibitory effects of Sox5/6/9 were rescued by treating with anti-PTHrP antibody. Moreover, Sox5/6/9 bound to the promoter region of the PTHrP gene and up-regulated PTHrP gene promoter activity. Interestingly, we also found that the Sox9 family members functionally collaborated with Ihh/Gli2 signaling to regulate PTHrP expression and chondrocyte differentiation. Our results provide novel evidence that Sox9 family members mediate endochondral ossification by up-regulating PTHrP expression in association with Ihh/Gli2 signaling.

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Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy

Cited by 243 publications

References 26 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling

Sox9 Family Members Negatively Regulate Maturation and Calcification of Chondrocytes through Up-Regulation of Parathyroid Hormone–related Protein

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