Autophagy Prior to Chondrocyte Cell Death During the Degeneration of Meckel's Cartilage

Yang, Ruigang; Zhang, Chi; Liu, Yong; Zhou, Hai-Hua; Li, Zubing

doi:10.1002/ar.22433

Cited by 23 publications

(24 citation statements)

References 28 publications

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“…Recent studies have demonstrated that autophagy is involved in certain bone and cartilage diseases, such as cervical disc degeneration (42), cartilage degeneration of the temporomandibular joint (23), degradation of Meckel's cartilage (43) and OA (44). However, the results regarding changes in autophagy and the specific role of autophagy in the progression of OA are sometimes contradictory (25,26).…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy in the progression of osteoarthritis: The autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis

Cheng

Meng

et al. 2017

International Journal of Molecular Medicine

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Accumulating evidence suggests that autophagy is closely related to the pathogenesis of osteoarthritis (OA). The aim of this study was to determine the changes in autophagy during the progression of OA and to elucidate the specific role of autophagy in OA. For this purpose, a cellular model of OA was generated by stimulating SW1353 cells with interleukin (IL)-1β and a rabbit model of OA was also established by an intra-articular injection of collagenase, followed by treatment with the autophagy specific inhibitor, 3-methyladenine (3-MA). Cell viability was analyzed by MTS assay, and the mRNA expression levels of matrix metalloproteinases (MMP)-13 and tissue inhibitor of metalloproteinase (TIMP)-1 were determined by RT-qPCR. Cartilage degeneration was examined under a light microscope, and autophagosome and chondrocyte degeneration was observed by transmission electron microscopy. The protein expression of Beclin-1 and light chain 3 (LC3)B was evaluated by western blot analysis and immunofluorescence staining. We found that the autophagy was enhanced during the early stages and was weakened during the late stages of experimental OA. The inhibition of autophagy by 3-MA significantly aggravated the degeneration of chondrocytes and cartilage in experimental OA. Our results thus determine the changes in autophagy during different stages of OA, as well as the role of impaired autophagy in the development of OA. Our data suggest that the regulation of autophagy may be a potential therapeutic strategy with which to attenuate OA.

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Section: Discussionmentioning

confidence: 99%

Role of autophagy in the progression of osteoarthritis: The autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis

Cheng

Meng

et al. 2017

International Journal of Molecular Medicine

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“…In surgically induced and age-related OA model, reduced autophagy and increase in apoptosis were observed [21]. Autophagy defect occured before chondrocyte cell death during Meckel cartilage degeneration [26]. Our present study also showed that knee joints from Vhl cKO mice with age-related and surgically induced OA displayed increased numbers of apoptotic chondrocytes and decreased expression of autophagy marker LC3II and Beclin1, suggesting a novel role of Vhl in maintaining cartilage homeostasis by regulating chondrocyte survival and autophagy.…”

Section: Discussionmentioning

confidence: 99%

Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis

Weng

Xie

et al. 2014

Osteoarthritis and Cartilage

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Objective To investigate the role of Vhl in maintaining the integrity of articular cartilage and in the development of experimental osteoarthritis (OA). Method Histology of articular cartilage and subchondral bone in both Vhl cKO and WT mice were analyzed by histopathology and micro-CT. Articular cartilage destruction and proteoglycan loss were scored in aged (12-month-old) mice as well as in mice with surgically induced OA. Apoptosis of cartilage in age-related and surgically induced OA was detected with TUNNEL assay. Expressions of VHL, Fas, LC-3, HIF-1α, HIF-2α, p-mTOR and MMP-13 in the knee joints were analyzed by immunostaining. Results No gross differences in cartilage were observed between Vhl cKO and WT mice at age 4 months. However, Vhl cKO mice displayed accelerated age-associated spontaneous OA and surgically induced OA. Cartilage destruction and proteoglycan loss were observed in the absence of Vhl. In addition, inactivation of Vhl resulted in up-regulation of HIF-2α and increased chondrocyte apoptosis and decreased expression of autophagy during OA development. Immunohistochemical staining also showed that Vhl deficiency led to increased expression of Fas, p-mTOR and MMP-13, and those genes were associated with cell apoptosis, autophagy and cartilage matrix breakdown, respectively. Conclusion Loss of Vhl in adult articular cartilage is associated with earlier dysregulation of cartilage homeostasis, characterized by an increased chondrocyte apoptosis, compromised chondrocyte autophagy, and an accelerated age-related and surgery-induced OA development. These results highlight the novel role of Vhl in maintaining joint homeostasis and OA development.

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“…Despite that the chondrocytes in this portion become hypertrophic, they do not express chondrogenic differentiation markers, such as Col X and Ihh (Chung et al, 1995; this study), suggesting an arrest of chondrogenic differentiation prior to degeneration. Previous studies have implicated multiple factors and cellular processes in degeneration and resorption of Meckel’s cartilage, including several matrix metalloproteinases (Ishizeki and Nawa, 2000; Sakakura et al, 2007a, 2007b), macrophages (Harada and Ishezeki, 1998; Sakakura et al, 2005; Tsuzurahara et al, 2011), and possible autophagy and apoptosis (Trichilis and Wroblewski, 1997; Yang et al, 2012). However, the underlying mechanism that is responsible for the arrest of chondrogenic differentiation and subsequent degeneration of Meckel’s cartilage remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…However, unlike the fate of those mesoderm-derived cartilaginous elements and other CNC-derived cartilages such as cranial base, the majority of Meckel’s cartilage does not develop further and becomes degenerated. While previous studies have revealed potential contributions of several factors and cellular processes to the disappearance/resorption (Trichilis and Wroblewski, 1997; Harada and Ishizeki, 1998; Sakakura et al, 2005, 2007a, 2007b; Tsuzurahara et al, 2011; Yang et al, 2012), signaling pathways that prevent further differentiation and trigger degeneration of Meckel’s cartilage remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Enhanced BMP signaling prevents degeneration and leads to endochondral ossification of Meckel′s cartilage in mice

Wang

Zheng

Chen

et al. 2013

Developmental Biology

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Meckel’s cartilage is a transient supporting tissue of the embryonic mandible in mammals, and disappears by taking different ultimate cell fate along the distal-proximal axis, with the majority (middle portion) undergoing degeneration and chondroclastic resorption. While a number of factors have been implicated in the degeneration and resorption processes, signaling pathways that trigger this degradation are currently unknown. BMP signaling has been implicated in almost every step of chondrogenesis. In this study, we used Noggin mutant mice as a model for gain-of-BMP signaling function to investigate the function of BMP signaling in Meckel’s cartilage development, with a focus on the middle portion. We showed that Bmp2 and Bmp7 are expressed in early developing Meckels’ cartilage, but their expression disappears thereafter. In contrast, Noggin is expressed constantly in Meckel’s cartilage throughout the entire gestation period. In the absence of Noggin, Meckel’s cartilage is significantly thickened attributing to dramatically elevated cell proliferation rate associated with enhanced phosphorylated Smad1/5/8 expression. Interestingly, instead of taking a degeneration fate, the middle portion of Meckel’s cartilage in Noggin mutants undergoes chondrogenic differentiation and endochondral ossification contributing to the forming mandible. Chondrocyte-specific expression of a constitutively active form of BMPRIa but not BMPRIa leads enlargement of Meckel’s cartilage, phenocopying the consequence of Noggin deficiency. Our results demonstrate that elevated BMP signaling prevents degeneration and leads to endochondral ossification of Meckel’s cartilage, and support the idea that withdrawal of BMP signaling is required for normal Meckel’s cartilage development and ultimate cell fate.

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Autophagy Prior to Chondrocyte Cell Death During the Degeneration of Meckel's Cartilage

Cited by 23 publications

References 28 publications

Role of autophagy in the progression of osteoarthritis: The autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis

Role of autophagy in the progression of osteoarthritis: The autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis

Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis

Enhanced BMP signaling prevents degeneration and leads to endochondral ossification of Meckel′s cartilage in mice

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