Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice

Bellini, Melina Rodrigues; Pest, M.A.; Miranda-Rodrigues, Manuela; Qin, Ling; Jeong, Jae Wook; Beier, Frank

doi:10.1186/s13075-020-02213-z

Cited by 9 publications

(6 citation statements)

References 69 publications

(101 reference statements)

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“…Depletion of MIG6 in ECs significantly increased VEGFA-induced phosphorylation at multiple sites of VEGFR2, indicating that various biological events mediated by VEGFR2 phosphorylation might be affected by MIG6 knockdown. The effects of MIG6 on phosphorylation of multiple tyrosine residues were also observed in the case of EGFR in which the first segment (337Ser-361Ser) of EGFR binding domain (EBD) in MIG6 was proposed to bind the EGFR kinase domain (Xu and Li 2021 ; Zhang et al 2007 ) and MIG6 overexpression attenuated the phosphorylation of Tyr1068 and Tyr1173 on EGFR (Bellini et al 2020 ; Descot et al 2009 ; Liu et al 2012 ). Given the regulatory role of MIG6 in the overall phosphorylation of these receptor kinases, it is possible that any biological effect observed in MIG6 knockdown cells may derive from a combination of signaling pathways involving multiple phosphorylation sites of the receptor.…”

Section: Discussionmentioning

confidence: 92%

Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

Xing

Huang

Chen

et al. 2022

J. Cell Commun. Signal.

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Although mitogen-inducible gene 6 (MIG6) is highly expressed in vascular endothelial cells, it remains unknown whether MIG6 affects vascular permeability. Here, we show for the first time a critical role of MIG6 in limiting vascular permeability. We unveil that genetic deletion of Mig6 in mice markedly increased VEGFA-induced vascular permeability, and MIG6 knockdown impaired endothelial barrier function. Mechanistically, we reveal that MIG6 inhibits VEGFR2 phosphorylation by binding to the VEGFR2 kinase domain 2, and MIG6 knockdown increases the downstream signaling of VEGFR2 by enhancing phosphorylation of PLCγ1 and eNOS. Moreover, MIG6 knockdown disrupted the balance between RAC1 and RHOA GTPase activation, leading to endothelial cell barrier breakdown and the elevation of vascular permeability. Our findings demonstrate an essential role of MIG6 in maintaining endothelial cell barrier integrity and point to potential therapeutic implications of MIG6 in the treatment of diseases involving vascular permeability. Graphical abstract Xing et al. (2022) investigated the critical role of MIG6 in vascular permeability. MIG6 deficiency promotes VEGFA-induced vascular permeability via activation of PLCγ1-Ca2+-eNOS signaling and perturbation of the balance in RAC1/RHOA activation, resulting in endothelial barrier disruption.

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Section: Discussionmentioning

confidence: 92%

Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

Xing

Huang

Chen

et al. 2022

J. Cell Commun. Signal.

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“…Our results are consistent with a recent publication analyzing mice overexpressing Mig6 in a chondrocyte-specific manner using Col2-Cre. (34) In these mice with reduced chondrogenic EGFR activity, articular cartilage appeared normal at 11 weeks of age but developed spontaneous OA at 12 months of age. Mice with cartilage-specific (Col2-Cre) or skeleton-specific (Prrx1-Cre) deletion of Mig6, which have enhanced EGFR activity, showed opposite phenotypes, such as thickened articular cartilage and increased proliferation of superficial layer chondrocytes.…”

Section: Discussionmentioning

confidence: 95%

EGFR Signaling Is Required for Maintaining Adult Cartilage Homeostasis and Attenuating Osteoarthritis Progression

Wei

Sun

et al. 2020

Journal of Bone and Mineral Research

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The uppermost superficial zone of articular cartilage is the first line of defense against the initiation of osteoarthritis (OA). We previously used Col2-Cre to demonstrate that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, plays an essential role in maintaining superficial chondrocytes during articular cartilage development. Here, we showed that EGFR activity in the articular cartilage decreased as mice age. In mouse and human OA samples, EGFR activity was initially reduced at the superficial layer and then resurged in cell clusters within the middle and deep zone in late OA. To investigate the role of EGFR signaling in postnatal and adult cartilage, we constructed an inducible mouse model with cartilage-specific EGFR inactivation (Aggrecan-CreER Egfr Wa5/flox , Egfr iCKO). EdU incorporation revealed that postnatal Egfr iCKO mice contained fewer slow-cycling cells than controls. EGFR deficiency induced at 3 months of age reduced cartilage thickness and diminished superficial chondrocytes, in parallel to alterations in lubricin production, cell proliferation, and survival. Furthermore, male Egfr iCKO mice developed much more severe OA phenotypes, including cartilage erosion, subchondral bone plate thickening, cartilage degeneration at the lateral site, and mechanical allodynia, after receiving destabilization of the medial meniscus (DMM) surgery. Similar OA phenotypes were also observed in female iCKO mice. Moreover, tamoxifen injections of iCKO mice at 1 month post-surgery accelerated OA development 2 months later. In summary, our data demonstrated that chondrogenic EGFR signaling maintains postnatal slow-cycling cells and plays a critical role in adult cartilage homeostasis and OA progression.

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“…Previous studies have shown that EGFR was critical for maintaining the superficial layer of articular cartilage and cartilage homeostasis [ 62 , 63 ]. Mitogen-inducible gene 6 (Mig-6) is identified as a negative regulator of the EGFR, and its overexpression could cause an OA-like phenotype and earlier OA in mice [ 64 ]. Activating EGFR mediated signaling pathways is believed to attenuate posttraumatic OA following loading and surgical injury in mice [ 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of EGFR as an essential regulator in chondrocytes ferroptosis of osteoarthritis using bioinformatics, in vivo, and in vitro study

Sun,

Peng,

Chen

et al. 2023

Heliyon

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Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice

Cited by 9 publications

References 69 publications

Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

EGFR Signaling Is Required for Maintaining Adult Cartilage Homeostasis and Attenuating Osteoarthritis Progression

Identification of EGFR as an essential regulator in chondrocytes ferroptosis of osteoarthritis using bioinformatics, in vivo, and in vitro study

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