Role of p53 in human chondrocyte apoptosis in response to shear strain

Hashimoto, Shingo; Nishiyama, Tomihiro; Hayashi, Shinya; Fujishiro, Takaaki; Takebe, K.; Kanzaki, Noriyuki; Kuroda, Ryosuke; Kurosaka, Masahiro

doi:10.1002/art.24706

Cited by 79 publications

(58 citation statements)

References 35 publications

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“…It is known that p53 induces cell death in articular as well as Meckel's cartilage (Trichilis and Wroblewski, 1997;Okazaki et al, 2003). In human chondrocyte culture, PFT treatment suppresses p-p53-Ser15 as well as chondrocyte apoptosis induced by mechanical stress (Hashimoto et al, 2009). Additional studies with PFT are necessary to identify the cell type that is responsible for the nasal phenotype.…”

Section: Discussionmentioning

confidence: 99%

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

et al. 2015

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Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-α, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

et al. 2015

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“…Furthermore, optimal mechanical stress stimulation was shown to maintain the structure and function of articular cartilage, whereas excessive mechanical force was shown to lead to a loss of cartilage and the onset of OA (31-33). In addition, we have previously demonstrated that excessive shear stress induces chodrocyte apoptosis via the p53 pathway (34).…”

Section: Discussionmentioning

confidence: 97%

Regulation of p38 MAPK phosphorylation inhibits chondrocyte apoptosis in response to heat stress or mechanical stress

Nishiyama

2011

Int J Mol Med

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Abstract. Activation of p38 MAPK has been associated with a stress response and with apoptotic processes. However, the function of p38 MAPK in chondrocytes is not clearly understood. In this study, we analyzed the expression of p38 MAPK in chondrocytes and investigated the function of p38 MAPK in response to heat stress and mechanical stress. chondrocytes were isolated from human cartilage and cultured. Expression of p38 and phosphorylated p38 in cartilage of patients with osteoarthritis (OA) was compared to those in normal cartilage by immunohistochemistry and Western blotting. Human knee chondrocytes were exposed to heat stress or mechanical stress. Normal knee chondrocytes were pre-treated with SB203580 or p38 small interfering RNA (siRNA) before induction of heat stress or mechanical stress. chondrocyte apoptosis was detected by TUNEL staining and Western blotting of cleaved caspases. OA and normal chondrocytes expressed p38; however, OA chondrocytes showed much higher phosphorylated p38 compared to normal chondrocytes. Heat stress or mechanical stress induced apoptosis and increased phosphorylated p38 in normal chondrocytes. The TUNEL positive cells and expression levels of phosphorylated p38 in response to stress decreased when chondrocytes were incubated with SB203580 or transfected with siRNA against p38. In conclusion, we have demonstrated that heat stress or mechanical stress increased chondrocyte apoptosis via phosphorylation of p38. Stress-induced chondrocyte apoptosis decreased due to inhibition of p38 MAPK activation. In contrast, the phosphorylation of p38 MAPK increased in OA chondrocytes. Our results show that down-regulation of p38 MAPK activation inhibits chondrocyte death induced by heat stress or mechanical stress.

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“…Threshold stresses and strains for cartilage matrix damage and cell death are shown to be dependent on rate of loading [56,59,86,87], duration of load [85,89], and magnitude of load [56,59,85,88,89]. However, maximum shear strain has been identified as one major failure mode for the cartilage matrix [57,58].…”

Section: Cartilage Matrix Damage and Chondrocyte Apoptosismentioning

confidence: 99%

“…show that there is a strong positive association between cartilage matrix damage and chondrocyte apoptosis [84], indicating that prolonged or large magnitude impact loading causing tissue damage also leads to cell death [56,59,85,86,87,88,89].…”

Section: Cartilage Matrix Damage and Chondrocyte Apoptosismentioning

confidence: 99%

“…However, maximum shear strain has been identified as one major failure mode for the cartilage matrix [57,58]. Cartilage apoptosis has been observed when specimens were subject to 2%, 5%, and 10% shear strains for 6 hours, and at 10% shear strain after only 2 hours [89]. Shear strain was also observed to cause cartilage matrix damage and chondrocyte apoptosis above 25% strain at a rate of 500/second [56].…”

Section: Cartilage Matrix Damage and Chondrocyte Apoptosismentioning

confidence: 99%

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Development and validation of a human knee joint finite element model for tissue stress and strain predictions during exercise

Wangerin¹

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Role of p53 in human chondrocyte apoptosis in response to shear strain

Cited by 79 publications

References 35 publications

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

Regulation of p38 MAPK phosphorylation inhibits chondrocyte apoptosis in response to heat stress or mechanical stress

Development and validation of a human knee joint finite element model for tissue stress and strain predictions during exercise

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