Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone

Maeda, Yukiko; Nakamura, Eiichiro; Nguyen, Minh‐Thanh; Suva, Larry J.; Swain, Frances L.; Razzaque, Mohammed S.; Mackem, Susan; Lanske, Beate

doi:10.1073/pnas.0608449104

Cited by 235 publications

(252 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

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: Animal Models Of Oamentioning

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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“…Because PTHrP activates the PPR and then Gsα, and because the KO of Gsα in the growth plate of mice leads to accelerated chondrocyte differentiation resembling that of the PPR KO (4,20), it is plausible that the growth plate closure in AHO and human heterozygosity for the PTHrP gene result from processes like those demonstrated here. Growth plate closure is also seen when Ihh is knocked out postnatally in the growth plate (21) or when hedgehog antagonists are administered to mice (22). Because Ihh stimulates PTHrP production in chondrocytes (1), this closure may involve mechanisms similar to those described here.…”

Section: Discussionmentioning

confidence: 83%

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Hanabusa

Chagin

Kobayashi

et al. 2010

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

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Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a lowphosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes.

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“…Skeletal elements formed through endochondral ossification are derived from cartilaginous templates that are replaced by osteoblast derived bone matrix. Decreases in bone mass are therefore frequently observed in mice with genetic mutations that impede the formation of the cartilaginous template through a disruption in chondrocyte biology (22)(23)(24). Accordingly, we anticipated that the osteosclerotic phenotype that we previously reported to be present in the Shn3 −/− strain would not be preserved in the chondrodysplastic Shn2/3-DKO mice (11).…”

Section: Resultsmentioning

confidence: 99%

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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Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone

Cited by 235 publications

References 26 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

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

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