Wwp2 maintains cartilage homeostasis through regulation of Adamts5

Mokuda, Sho; Nakamichi, Ryo; Matsuzaki, Takashi; Ito, Yoshiaki; Sato, Tempei; Miyata, Koichiro; Inui, Masafumi; Olmer, Merissa; Sugiyama, Eiji; Lotz, Martin; Asahara, Hiroshi

doi:10.1038/s41467-019-10177-1

Cited by 91 publications

(78 citation statements)

References 60 publications

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“…A more precise analysis of Wwp2 and miR-140 recently reported that Wwp2 mutant mice had no craniofacial abnormalities [53], in contrast to a previous study that observed impaired skull formation in Wwp2-KO mice [54]. Together, these results indicate that miR-140, rather than Wwp2, is crucial for craniofacial development and chondrogenesis in addition to its suggested role in cartilage homeostasis [55]. These investigations highlight the difficulties in dissecting the functions of host genes and their miR.…”

Section: Micro-rna 140 (Mir-140) and Osteoarthritismentioning

confidence: 78%

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Nishimura

Hata

Takahata

et al. 2020

IJMS

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Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

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Section: Micro-rna 140 (Mir-140) and Osteoarthritismentioning

confidence: 78%

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Nishimura

Hata

Takahata

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…A more precise analysis of Wwp2 and miR-140 recently reported that Wwp2 mutant mice had no craniofacial abnormalities [47], in contrast to another study that observed impaired skull formation in miR-140 KO mice, as well as in Wwp2 and miR-140 double KO mice [47]. Together, these results indicate that miR-140, rather than Wwp2, is crucial for craniofacial development and chondrogenesis, in addition to its suggested role in cartilage homeostasis [49]. These investigations highlight the difficulties in dissecting the functions of host genes and their microRNA.…”

Section: Mir-140 and Osteoarthritismentioning

confidence: 78%

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Nishimura¹,

Hata²,

Takahata³

et al. 2020

Preprint

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Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. IL-1β also leads to osteoarthritis through NF-ĸB, IκBζ, and Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and TNFα play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as BMP, FGF, PTHrP, and Indian hedgehog, play roles regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling cause genetic disorders in cartilage and skeletal tissues. FOP, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. mTOR inhibitors were found to prevent ectopic ossification by ACVR1 mutations. ACH and related diseases are autosomal genetic diseases, which manifest severe dwarfism. CNP is currently the most promising therapy for ACH. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels sheds light on the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

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“…26,27 Currently, WWP2 is considered to be involved in various life activities, such as development and ossification. 16,[19][20][21][22] In previous studies, WWP2 was discovered to be highly expressed in diabetic cardiomyopathic heart. 28 In primary cardiac fibroblasts, TGFβ1 irritates the N-terminal subtype of WWP2 to enter the nucleus, subsequently strengthening the activity of WWP2-FL to promote the combining with Smad2, and may promote its monoubiquitination, thus activating the downstream Pro-fibrogenic gene programme.…”

Section: Discussionmentioning

confidence: 99%

“…The E3 ubiquitin ligase WWP2 controls many biological processes such as the cell cycle, cell division, immune response, antigen presentation, apoptosis and cell signalling. [16][17][18][19] WWP2 not only degrades substrates, but also regulates genes post-transcriptionally. 20 Studies have demonstrated that WWP2 dysfunction can cause many diseases, including maxillofacial deformity, skeleton damage and embryonic dysplasia.…”

mentioning

confidence: 99%

WWP2 regulates SIRT1‐STAT3 acetylation and phosphorylation involved in hypertensive angiopathy

Zhang

You

Tian

et al. 2020

J Cellular Molecular Medi

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WWP2 is a HECT‐type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its function and regulatory mechanism in vascular smooth muscle cells (VSMCs) are still unknown. Here, we clarified the role of WWP2 in the regulation of SIRT1‐STAT3 and the impact of this regulatory process in VSMCs. We demonstrated that WWP2 expression was significantly increased in angiotensin II‐induced VSMCs model. Knockdown of WWP2 significantly inhibited angiotensin II‐induced VSMCs proliferation, migration and phenotypic transformation, whereas overexpression of WWP2 had opposite effects. In vivo experiments showed that vascular smooth muscle‐specific WWP2 knockout mice significantly relieved angiotensin II‐induced hypertensive angiopathy. Mechanistically, mass spectrometry and co‐immunoprecipitation assays identified that WWP2 is a novel interacting protein of SIRT1 and STAT3. Moreover, WWP2 formed a complex with SIRT1‐STAT3, inhibiting the interaction between SIRT1 and STAT3, then reducing the inhibitory effect of SIRT1 on STAT3, ensuing promoting STAT3‐K685 acetylation and STAT3‐Y705 phosphorylation in angiotensin II‐induced VSMCs and mice. In conclusion, WWP2 modulates hypertensive angiopathy by regulating SIRT1‐STAT3 and WWP2 suppression in VSMCs can alleviate hypertensive angiopathy vitro and vivo. These findings provide new insights into the treatment of hypertensive vascular diseases.

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Wwp2 maintains cartilage homeostasis through regulation of Adamts5

Cited by 91 publications

References 60 publications

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

WWP2 regulates SIRT1‐STAT3 acetylation and phosphorylation involved in hypertensive angiopathy

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