Potential role of WISP3 (CCN6) in regulating the accumulation of reactive oxygen species

Miller, D. Josh; Sen, Malini

doi:10.1016/j.bbrc.2007.01.114

Cited by 18 publications

(28 citation statements)

References 24 publications

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“…In the light of previous findings demonstrating CCN6 as regulating total cellular ROS (Miller and Sen, 2007;Repudi et al, 2013), we examined if CCN6 influences mitochondrial ROS accumulation in association with mitochondrial ATP synthesis and Ca 2+ at the steady state. Our investigation was furthermore prompted by several reports documenting the interrelation of mitochondrial ROS, ATP and Ca 2+ (Brookes et al, 2004;Lehninger, 1970).…”

Section: +mentioning

confidence: 99%

“…C-28/I2 chondrocyte cells and HEK293 cells were maintained in Dulbecco's modified Eagle's medium (DMEM; Invitrogen) supplemented with 10% FBS, penicillin (1 unit ml −1 ), streptomycin (1 μg ml −1 ) and glutamine (2 mM) (Invitrogen) in a humidified incubator maintaining 37°C temperature and 5% CO 2 (Miller and Sen, 2007;Repudi et al, 2013). The C-28/I2 cell line was generated through retroviral infection of human juvenile costal cartilage with SV40 large T antigen (Goldring et al, 1994).…”

Section: Cell Culturementioning

confidence: 99%

“…CCN6, or Wnt-induced signaling protein 3 (WISP3), is a 354-aminoacid protein that can function both intracellularly and extracellularly (Brigstock et al, 2003;Davis et al, 2006;Miller and Sen, 2007;Pal et al, 2012;Perbal, 2013;Repudi et al, 2013). WISP3 gets its name from its sequence homology with other WISP (CCN)-family members that are induced by Wnt1 (Pennica et al, 1998;Sen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…On account of the established link of CCN6 with PPRD, a comprehensive characterization of its function at the molecular level is important. CCN6 has been shown to modulate both IGF1-induced as well as basal expression of cartilage hypertrophy markers, such as reactive oxygen species (ROS) (Miller and Sen, 2007;Repudi et al, 2013). Other functions of CCN6 that might be useful in the context of cartilage growth and/or maintenance remain to be deciphered.…”

Section: Introductionmentioning

confidence: 99%

“…Given its influence on total cellular ROS accumulation (Miller and Sen, 2007;Repudi et al, 2013), we wanted to investigate if CCN6 controls mitochondrial ROS by regulating the mitochondrial electron transport chain (ETC). Perhaps the loss of a functional cartilage and the aberrant matrix mineralization associated with CCN6 mutations in individuals with PPRD (Dalal et al, 2012;Ekbote et al, 2013;Garcia Segarra et al, 2012;Hurvitz et al, 1999;Liu et al, 2015;Luo et al, 2015;Yang et al, 2013) are due to an imbalance in cell differentiation and/or hypertrophy, arising partly from altered mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

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CCN6 regulates mitochondrial function

Patra

Mahata

Padhan

et al. 2016

Journal of Cell Science

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Despite established links of CCN6, or Wnt induced signaling protein-3 (WISP3), with progressive pseudo rheumatoid dysplasia, functional characterization of CCN6 remains incomplete. In light of the documented negative correlation between accumulation of reactive oxygen species (ROS) and CCN6 expression, we investigated whether CCN6 regulates ROS accumulation through its influence on mitochondrial function. We found that CCN6 localizes to mitochondria, and depletion of CCN6 in the chondrocyte cell line C-28/I2 by using siRNA results in altered mitochondrial electron transport and respiration. Enhanced electron transport chain (ETC) activity of CCN6-depleted cells was reflected by increased mitochondrial ROS levels in association with augmented mitochondrial ATP synthesis, mitochondrial membrane potential and Ca 2+. Additionally, CCN6-depleted cells display ROS-dependent PGC1α (also known as PPARGC1A) induction, which correlates with increased mitochondrial mass and volume density, together with altered mitochondrial morphology. Interestingly, transcription factor Nrf2 (also known as NFE2L2) repressed CCN6 expression. Taken together, our results suggest that CCN6 acts as a molecular brake, which is appropriately balanced by Nrf2, in regulating mitochondrial function.

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Section: +mentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CCN6 regulates mitochondrial function

Patra

Mahata

Padhan

et al. 2016

Journal of Cell Science

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The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals

Segarra

Mittaz

Campos-Xavier

et al. 2012

American J of Med Genetics Pt C

121

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Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.

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CCN6 mutation detection in Chinese patients with progressive pseudo‐rheumatoid dysplasia and identification of four novel mutations

Wang

Xiao

Yang

et al. 2020

Molec Gen & Gen Med

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Background:No formal diagnostic criteria for progressive pseudo-rheumatoid dysplasia (PPD) are available because of insufficient clinical data, which results in that PPD is often misdiagnosed with other diseases. Whole exome sequencing (WES) and Sanger sequencing were employed to reveal the novel mutations on CCN6 of five patients with PPD from China in order to increase the clinical data of PPD. Methods: Four suspected PPD pedigrees containing five patients in total were collected from 1998 to 2018 in our medical center. The phenotypes of each suspected PPD case were recorded in detail, and peripheral blood samples were collected for subsequent sequencing. Genomic DNA was extracted from peripheral blood samples, and Agilent liquid phase chip capture system was utilized for efficient enrichment of whole exome region DNA. After acquiring raw sequenced reads of whole exome region, bioinformatics analysis was completed in conjunction with reference or genome sequence (GRCh37/hg19). Sanger sequencing was performed to identify the results of WES. Results: In total, four novel PPD-related mutation sites in CCN6 gene were identified including (CCN6):c.643 + 2T>C, (CCN6):c.1064_1065dupGT(p. Gln356ValfsTer33), (CCN6):c.1064G > A), and exon4:c.670dupA:p.W223fs. Conclusion:Our findings increase the clinical data of PPD including the CCN6 mutation spectrum, the clinical symptoms and signs. Moreover, the study highlights the utility of WES in reaching definitive diagnoses for PPD.

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Potential role of WISP3 (CCN6) in regulating the accumulation of reactive oxygen species

Cited by 18 publications

References 24 publications

CCN6 regulates mitochondrial function

CCN6 regulates mitochondrial function

The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals

CCN6 mutation detection in Chinese patients with progressive pseudo‐rheumatoid dysplasia and identification of four novel mutations

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