Indian Hedgehog Signaling Regulates Transcription and Expression of Collagen Type X via Runx2/Smads Interactions

Amano, Katsuhiko; Densmore, Michael; Nishimura, Riko; Lanske, Beate

doi:10.1074/jbc.m114.570507

Cited by 59 publications

(64 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, Ihh pathway antagonist, Hedgehog interacting protein (Hhip), is down-regulated whereas Dispatched-1 (Disp1), a protein involved in Ihh secretion, is up-regulated (32). Interestingly, expression of Collagen 10α1 (Col10α1), a hypertrophic chondrocyte marker, is up-regulated as well (33). These data suggest that fracture activates hedgehog signaling in f-BCSPs.…”

Section: Significancementioning

confidence: 63%

Identification and characterization of an injury-induced skeletal progenitor

Marecic

Tevlin

McArdle

et al. 2015

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

View full text Add to dashboard Cite

The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice. The f-BCSP possesses significantly enhanced skeletogenic potential compared with BCSPs harvested from uninjured bone. It also recapitulates many gene expression patterns involved in perinatal skeletogenesis. Our results indicate that the skeletal progenitor population is functionally stratified, containing distinct subsets responsible for growth, regeneration, and repair. Furthermore, our findings suggest that injury-induced changes to the skeletal stem and progenitor microenvironments could activate these cells and enhance their regenerative potential.osteogenesis | skeletal stem/progenitor cell | fracture healing | regeneration | injury activation

show abstract

Section: Significancementioning

confidence: 63%

Identification and characterization of an injury-induced skeletal progenitor

Marecic

Tevlin

McArdle

et al. 2015

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

View full text Add to dashboard Cite

show abstract

“…Specifically, the TGF‐β pathway has been shown to be involved in SMO‐independent GLI2 activation (25). GLI proteins may contribute to the development of pulmonary fibrosis in several ways; namely, they may: 1 ) control the expression of proproliferative and antiapoptotic genes (31), 2 ) regulate collagen production (32), 3 ) promote epithelial to mesenchymal transition by inducing the expression of Snail (33), and 4 ) foster differentiation of fibroblasts into myofibroblasts by modulating the transcriptional activity of a ‐SMA gene (34). Because GLI proteins may be regulated by growth factors/signaling cascades other than Hh ligands through noncanonical mechanisms (15), they are perfectly suited to fulfill a master regulator function in a vast array of profibrotic processes.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors

et al. 2017

View full text Add to dashboard Cite

Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown. Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway. We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription. Consequently, pirfenidone decreases overall Hh pathway activity in patients with IPF and in patient-derived primary lung fibroblasts and leads to diminished levels of Hh target genes, such as GLI1, Hh receptor Patched-1, α-smooth muscle actin, and fibronectin, and to reduced cell migration and proliferation. Interestingly, Hh-triggered TGF-β1 expression potentiated Hh responsiveness of primary lung fibroblasts by elevating the available pool of glioma-associated oncogene homolog (GLI)1/GLI2, thus creating a vicious cycle of amplifying fibrotic processes. Because GLI transcription factors are not only crucial for Hh-mediated changes but are also required as mediators of TGF-β signaling, our findings suggest that pirfenidone exerts its clinically beneficial effects through dual Hh/TGF-β inhibition by targeting the GLI2 protein.-Didiasova, M., Singh, R., Wilhelm, J., Kwapiszewska, G., Wujak, L., Zakrzewicz, D., Schaefer, L., Markart, P., Seeger, W., Lauth, M., Wygrecka, M. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors.

show abstract

“…Therefore, it is likely that Hh signaling does not regulate the initiation of mineralization, but rather controls the location of the mineralization front, the development of a mineral gradient, and/or the accumulation of mineral. Furthermore, Hh signaling may regulate proteins that participate in mineralization: Gli1 can control expression of osteopontin (Yoon, et al 2002), a known regulator of mineral growth, and IHH can regulate Col10a1 expression via Runx2/Smads interactions (Amano, et al 2014), which promotes mineralization through its interaction with matrix vesicles. In fact, these mice display smaller crystal size (Schwartz, et al 2015) in the mineralized fibrocartilage, suggesting that crystal growth was impaired.…”

Section: Discussionmentioning

confidence: 99%

Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis

Dyment

Breidenbach

Schwartz

et al. 2015

Developmental Biology

106

145

View full text Add to dashboard Cite

The sequence of events that leads to the formation of a functionally graded enthesis is not clearly defined. The current study demonstrates that clonal expansion of Gdf5 progenitors contributes to linear growth of the enthesis. Prior to mineralization, Col1+ cells in the enthesis appose Col2+ cells of the underlying primary cartilage. At the onset of enthesis mineralization, cells at the base of the enthesis express alkaline phosphatase, Indian hedgehog, and ColX as they mineralize. The mineralization front then extends towards the tendon midsubstance as cells above the front become encapsulated in mineralized fibrocartilage over time. The hedgehog (Hh) pathway regulates this process, as Hh-responsive Gli1+ cells within the developing enthesis mature from unmineralized to mineralized fibrochondrocytes in response to activated signaling. Hh signaling is required for mineralization, as tissue-specific deletion of its obligate transducer Smoothened in the developing tendon and enthesis cells leads to significant reductions in the apposition of mineralized fibrocartilage. Together, these findings provide a spatiotemporal map of events – from expansion of the embryonic progenitor pool to synthesis of the collagen template and finally mineralization of this template – that leads to the formation of the mature zonal enthesis. These results can inform future tendon-to-bone repair strategies to create a mechanically functional enthesis in which tendon collagen fibers are anchored to bone through mineralized fibrocartilage.

show abstract

Indian Hedgehog Signaling Regulates Transcription and Expression of Collagen Type X via Runx2/Smads Interactions

Cited by 59 publications

References 47 publications

Identification and characterization of an injury-induced skeletal progenitor

Identification and characterization of an injury-induced skeletal progenitor

Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors

Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis

Contact Info

Product

Resources

About