AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes

Wang, Zhongyi; Tang, Jinxin; Liu, Ying; Wang, Yu; Guo, Yi; Tu, Qisheng; Chen, Jake Y.; Wang, Chen

doi:10.1016/j.yexcr.2019.111757

Cited by 12 publications

(10 citation statements)

References 72 publications

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“…Even though not in cancer models, additional studies further support the functional p44/42 MAPK role in either AdipoR-or adiponectin-mediated effects (Koskinen et al, 2011;Zhang et al, 2011;Alvarez et al, 2012;Wang et al, 2020). In this respect, Wang and coworkers have recently proved that ameliorating cell viability, apoptosis, and reactive oxygen species (ROS) production, AdipoR stimulates bone regeneration in ATDC5 cells via p44/42 MAPK pathway (Wang et al, 2020). Interestingly, when p44/42 MAPK was irreversibly suppressed by PD98059, AdipoR failed to rescue impaired apoptosis and chondrogenesis of cells.…”

Section: Discussionmentioning

confidence: 95%

“…In accordance with Akimoto's results (Akimoto et al, 2018), herein we demonstrated that p44/42 MAPK activation is needed to allow a proper AdipoR antitumor action and combination outcome. Even though not in cancer models, additional studies further support the functional p44/42 MAPK role in either AdipoR-or adiponectin-mediated effects (Koskinen et al, 2011;Zhang et al, 2011;Alvarez et al, 2012;Wang et al, 2020). In this respect, Wang and coworkers have recently proved that ameliorating cell viability, apoptosis, and reactive oxygen species (ROS) production, AdipoR stimulates bone regeneration in ATDC5 cells via p44/42 MAPK pathway (Wang et al, 2020).…”

Section: Discussionmentioning

confidence: 97%

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Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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“…For example, TBHP-induced chondrocyte apoptosis and extracellular matrix degradation were prevented by mangiferin in mouse OA by restoring autophagy [11]. Adipo-Ron, an adiponectin receptor agonist, reduced the calcification of chondrocytes associated with OA by promoting autophagy [12,13]. Recently, chondrocyte autophagy has gradually become a hotspot in OA research, but the regulatory mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

miR-31-5p/SOX4 Axis Affects Autophagy and Apoptosis of Chondrocytes by Regulating Extracellular Regulated Protein Kinase/Mechanical Target of Rapamycin Kinase Signalling

Wang³

et al. 2021

Pathobiology

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Background: Osteoarthritis (OA) is a common type of degenerative joint diseases that is regulated by a combination of complex intercellular signals and modulators, including non-coding RNAs. Mounting evidence suggests that miR-31-5p is physiologically involved in the regulation of chondrocytes, but the mechanism remains unclear. Methods: Expression levels of miR-31-5p and SOX4 in OA cartilage tissues and in IL-1β-stimulated chondrocytes were examined by quantification polymerase chain reaction (q-PCR) or immunohistochemistry assays. Cell proliferation and apoptosis were detected by Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Expression of LC3 was detected using immunofluorescence staining. Expressions of autophagy-related proteins and extracellular regulated protein kinase (ERK)/mechanical target of rapamycin kinase (mTORC1) signal-related proteins were measured by Western blot analysis. Molecular interaction was validated by dual luciferase reporter assay. Results: Downregulation of miR-31-5p and upregulation of SOX4 were observed in both OA patients and OA chondrocytes. Mechanistic experiments revealed that miR-31-5p negatively modulated SOX4 expression by directly targeting its 3′- untranslated region. Moreover, overexpression of miR-31-5p suppressed the activation of mTORC1 in an ERK-dependent manner by inhibiting SOX4. Further functional experiments demonstrated that overexpressing miR-31-5p in OA chondrocytes markedly promoted its proliferation and autophagy while inhibiting apoptosis. However, these effects were abolished by overexpression of SOX4 or treatment with 3BDO, an mTOR activator. Conclusion: These results demonstrated that miR-31-5p enhanced survival and autophagy of OA chondrocytes through inactivation of mTORC1 via directly targeting SOX4, suggesting that miR-31-5p may play a protective role in OA progression.

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“…In this study, DIO mice were utilized as we and others described ( Zhang et al, 2014 ; Yu et al, 2015 ; Fang et al, 2019 ; Wu et al, 2019 ; Wang et al, 2020 ; Harris et al, 2021 ; Qiu et al, 2021 ; Wu et al, 2022 ). These mice serve as an animal model of obesity and potential pre-T2D with elevated blood glucose and impaired glucose tolerance for a variety of metabolic studies including obesity, hyperglycemia, dyslipidemia, and glucose tolerance in T2D.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of a Novel Long Noncoding RNA that Regulates Osteogenesis in Diet-Induced Obesity Mice

Qiu

et al. 2022

Front. Cell Dev. Biol.

Self Cite

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As a precursor to type 2 diabetes mellitus (T2D), obesity adversely alters bone cell functions, causing decreased bone quality. Currently, the mechanisms leading to alterations in bone quality in obesity and subsequently T2D are largely unclear. Emerging evidence suggests that long noncoding RNAs (lncRNAs) participate in a vast repertoire of biological processes and play essential roles in gene expression and posttranscriptional processes. Mechanistically, the expression of lncRNAs is implicated in pathogenesis surrounding the aggregation or alleviation of human diseases. To investigate the functional link between specific lncRNA and obesity-associated poor bone quality and elucidate the molecular mechanisms underlying the interaction between the two, we first assessed the structure of the bones in a diet-induced obese (DIO) mouse model. We found that bone microarchitecture markedly deteriorated in the DIO mice, mainly because of aberrant remodeling in the bone structure. The results of in vitro mechanistic experiments supported these observations. We then screened mRNAs and lncRNAs from DIO bones and functionally identified a specific lncRNA, Gm15222. Further analyses demonstrated that Gm15222 promotes osteogenesis and inhibits the expression of adipogenesis-related genes in DIO via recruitment of lysine demethylases KDM6B and KDM4B, respectively. Through this epigenetic pathway, Gm15222 modulates histone methylation of osteogenic genes. In addition, Gm15222 showed a positive correlation with the expression of a neighboring gene, BMP4. Together, the results of this study identified and provided initial characterization of Gm15222 as a critical epigenetic modifier that regulates osteogenesis and has potential roles in targeting the pathophysiology of bone disease in obesity and potential T2D.

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AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes

Cited by 12 publications

References 72 publications

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

miR-31-5p/SOX4 Axis Affects Autophagy and Apoptosis of Chondrocytes by Regulating Extracellular Regulated Protein Kinase/Mechanical Target of Rapamycin Kinase Signalling

Identification and Characterization of a Novel Long Noncoding RNA that Regulates Osteogenesis in Diet-Induced Obesity Mice

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