The Hedgehog Signaling Pathway in Ischemic Tissues

Giarretta, Igor; Gaetani, Eleonora; Bigossi, Margherita; Tondi, Paolo; Asahara, Takayuki; Pola, Roberto

doi:10.3390/ijms20215270

Cited by 10 publications

(3 citation statements)

References 80 publications

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“… 44 Hh signaling pathway is known to regulate cell differentiation and migration during embryonic development but in post-natal life, the Hh signaling can be recapitulated under several pathological conditions, including cardiac ischemia. 45 The absence of tissue specific Hh signalling components reduces proangiogenic gene expression and thus loss of coronary vasculature that leads to cardiomyocyte cell death and ventricular failure. The presence of the Hh signalling pathway may protect and limit the extent of myocardial ischemic damage.…”

Section: Discussionmentioning

confidence: 99%

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis

et al. 2021

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“…5 Together with inflammation, regenerative mechanisms are triggered by OA chondrocytes presumably as an attempt to repair the damaged tissue, such as the reactivation of signalling pathways operating during endochondral ossification of the growth plate, as Indian Hedgehog (IHH), WNT or NOTCH signaling. 1,6,7 That is the reason why OA chondrocytes with this gene expression pattern are known as hypertrophiclike chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify cartilage damage in osteoarthritis

et al. 2022

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Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (Evc cKO ) model of OA. For this purpose, OA was induced by surgical knee destabilization in wild-type (WT) and Evc cKO adult mice, and healthy WT mice were used as controls (n = 10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot.Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1 beta as an inflammatory insult. Our results showed that tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not

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“…In turn, these cytokines induce the release of active metalloproteinases (MMP), aggrecanases and different proinflammatory mediators which activate the catabolic program characteristic of this disease (5). Together with inflammation, regenerative mechanisms are triggered by OA chondrocytes presumably as an attempt to repair the damagedtissue, such as the reactivation of signalling pathways operating during endochondral ossification of the growth plate, as Indian Hedgehog (IHH), WNT or NOTCH signaling (1,6,7).…”

Section: Introductionmentioning

confidence: 99%

Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify osteoarthritis progression

Lamuedra

Gratal

Calatrava

et al. 2021

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BackgroundChondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO) model of OA.MethodsOA was induced by surgical knee destabilization in wild-type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n=10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1β as an inflammatory insult.ResultsTamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM-EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. Hypertrophic – IHH – and inflammatory – COX-2 – markers co-localized in OA cartilage samples.ConclusionsTamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM-EvccKO mice, but it did not ameliorate cartilage damage. Our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.

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The Hedgehog Signaling Pathway in Ischemic Tissues

Cited by 10 publications

References 80 publications

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis

Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify cartilage damage in osteoarthritis

Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify osteoarthritis progression

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