mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis

Zhang, H.; Wang, H.; Zeng, Chun; Yan, Bo; Ouyang, Jiahong; Liu, X.; Sun, Qi-Shun; Zhao, Chang; Fang, Hang; Pan, Jinhe; Xie, Denghui; Yang, Junjun; Zhang, T.; Bai, Xiaochun; Cai, Daozhang

doi:10.1016/j.joca.2016.12.024

Cited by 61 publications

(66 citation statements)

References 38 publications

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“…Previous studies have established that activation of mTORC1 inhibits autophagy to promote articular chondrocyte apoptosis during OA development 41 42. Our previous study demonstrated the key role of the chondrocyte mTORC1 pathway in regulating cell proliferation and differentiation in OA 29. We also found that chondrocyte mTORC1 promoted OA partially through formation of vascular endothelial growth factor-A-stimulated subchondral H-type vessels 43.…”

Section: Discussionmentioning

confidence: 65%

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

et al. 2018

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ObjectivesTo investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA).MethodsSynovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA.ResultsM1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of β-catenin signalling in chondrocytes.ConclusionsSynovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment.

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Section: Discussionmentioning

confidence: 65%

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

et al. 2018

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“…Meanwhile, suppressing mTORC1 activity significantly ameliorated IL-1b-induced apoptosis and senescence of NP cells 12,13 . In addition, cartilage-specific tuberous sclerosis complex 1 (Tsc1, mTORC1 upstream inhibitor) knockout (TSC1CKO) mice showed spontaneous osteoarthritis (OA) with aberrant chondrocyte proliferation and hypertrophic differentiation 33 . These researches indicated that the declined activity of TFEB might be a consequence of aberrant mTORC1 activity in IVDD, which of course requires further experimental validation.…”

Section: Discussionmentioning

confidence: 99%

TFEB protects nucleus pulposus cells against apoptosis and senescence via restoring autophagic flux

Zheng

Pan

Zhan

et al. 2019

Osteoarthritis and Cartilage

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s u m m a r yObjective: Excessive apoptosis and senescence of nucleus pulposus (NP) cells are major pathological changes in intervertebral disc degeneration (IVDD) development; previous studies demonstrated pharmacologically or genetically stimulation of autophagy may inhibit apoptosis and senescence in NP cells. Transcription factor EB (TFEB) is a master regulator of autophagic flux via initiating autophagy-related genes and lysosomal biogenesis. This study was performed to confirm whether TFEB was involved in IVDD development and its mechanism. Methods: TFEB activity was detected in NP tissues in puncture-induced rat IVDD model by immunofluorescence as well as in tert-Butyl hydroperoxide (TBHP), the reactive oxygen species (ROS) donor to induce oxidative stress, treated NP cells by western blot. After TFEB overexpression in NP cells with lentivirus transfection, autophagic flux, apoptosis and senescence percentage were assessed. In in vivo study, the lentivirus-normal control (LV-NC) or lentivirus-TFEB (LV-TFEB) were injected into the center space of the NP tissue, after 4 or 8 weeks, Magnetic resonance imaging (MRI), X ray, Hematoxylin-Eosin (HE) and Safranin O staining were used to evaluate IVDD grades. Results: The nuclear localization of TFEB declined in degenerated rat NP tissue as well as in TBHP treated NP cells. Applying lentivirus to transfect NP cells, TFEB overexpression restored the TBHP-induced autophagic flux blockage and protected NP cells against apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Furthermore, TFEB overexpression ameliorates the puncture-induced IVDD development in rats. Conclusions: Experimental IVDD inhibited the TFEB activity. TFEB overexpression suppressed TBHPinduced apoptosis and senescence via autophagic flux stimulation in NP cell and alleviates punctureinduced IVDD development in vivo.

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“…Moreover, the reduced expression of the mTOR endogenous inhibitor REDD-1 has been found in OA and aged cartilage [98]. Another recent study showed that TSC1 knockout, associated with hyperactivation of TORC-1, provokes an OA-related phenotype in cartilage, possibly connected to the downregulation of two receptors involved in chondrocyte proliferation and differentiation: the fibroblast growth factor receptor 3 (FGFR-3) and parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PPR) [99]. Located upstream mTOR, the transcription factor peroxisome proliferator-activated receptor gamma (PPAR- γ ) regulates cartilage homeostasis, since its deficiency was found to be associated to increased TORC-1 signalling, impaired autophagy, and OA [100].…”

Section: Autophagy In Oamentioning

confidence: 99%

MicroRNAs and Autophagy: Fine Players in the Control of Chondrocyte Homeostatic Activities in Osteoarthritis

D’Adamo

Cetrullo

Minguzzi

et al. 2017

Oxidative Medicine and Cellular Longevity

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Osteoarthritis (OA) is a debilitating degenerative disease of the articular cartilage with a multifactorial etiology. Aging, the main risk factor for OA development, is associated with a systemic oxidative and inflammatory phenotype. Autophagy is a central housekeeping system that plays an antiaging role by supporting the clearance of senescence-associated alterations of macromolecules and organelles. Autophagy deficiency has been related to OA pathogenesis because of the accumulation of cellular defects in chondrocytes. Microribonucleic acids (microRNAs or miRs) are a well-established class of posttranscriptional modulators belonging to the family of noncoding RNAs that have been identified as key players in the regulation of cellular processes, such as autophagy, by targeting their own cognate mRNAs. Here, we present a state-of-the-art literature review on the role of miRs and autophagy in the scenario of OA pathogenesis. In addition, a comprehensive survey has been performed on the functional connections of the miR network and the autophagy pathway in OA by using “microRNA,” “autophagy,” and “osteoarthritis” as key words. Discussion of available evidence sheds light on some aspects that need further investigation in order to reach a more comprehensive view of the potential of this topic in OA.

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mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis

Abstract: mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.

Cited by 61 publications

References 38 publications

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2

TFEB protects nucleus pulposus cells against apoptosis and senescence via restoring autophagic flux

MicroRNAs and Autophagy: Fine Players in the Control of Chondrocyte Homeostatic Activities in Osteoarthritis

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