Rapamycin prevents the intervertebral disc degeneration via inhibiting differentiation and senescence of annulus fibrosus cells

Gao, Changhong; Ning, Bin; Sang, Chenglin; Zhang, Ying

doi:10.18632/aging.101364

Cited by 34 publications

(28 citation statements)

References 41 publications

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“…At present, there are also cytokine-neutralizing antibody therapies for use against senescent cells. Rapamycin is an mTOR inhibitor, and treatment with rapamycin could reduce the expression of MMP-3, MMP-13, IL-1 and IL-6 in rabbit annulus fibrosus stem cells (AFSCs), inhibit mTOR signaling, reduce SASP secretion, regulate the inflammatory response in vivo, and inhibit cell senescence, thus showing potential for the treatment of age-related diseases, 204 including OA.…”

Section: Targeting Of the Subchondral Bone Microenvironment For Oa Anmentioning

confidence: 99%

Subchondral bone microenvironment in osteoarthritis and pain

et al. 2021

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Osteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.

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Section: Targeting Of the Subchondral Bone Microenvironment For Oa Anmentioning

confidence: 99%

Subchondral bone microenvironment in osteoarthritis and pain

et al. 2021

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“…Thus, altering the metabolic status of senescence cells may be an important strategy for eliminating the deleterious effects of senescence. Indeed, metabolism-targeting drugs (e.g., rapamycin and etomoxir) have been used to eliminate senescent tumor cells following chemotherapy, leading to suppressed SASP production [ 43 , 46 , 47 ]. Humanin and MOTS-c impact cellular energetics.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Kim

Mehta

Wan

et al. 2018

Aging

109

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Cellular senescence is a complex cell fate response that is thought to underlie several age-related pathologies. Despite a loss of proliferative potential, senescent cells are metabolically active and produce energy-consuming effectors, including senescence-associated secretory phenotypes (SASPs). Mitochondria play crucial roles in energy production and cellular signaling, but the key features of mitochondrial physiology and particularly of mitochondria-derived peptides (MDPs), remain underexplored in senescence responses. Here, we used primary human fibroblasts made senescent by replicative exhaustion, doxorubicin or hydrogen peroxide treatment, and examined the number of mitochondria and the levels of mitochondrial respiration, mitochondrial DNA methylation and the mitochondria-encoded peptides humanin, MOTS-c, SHLP2 and SHLP6. Senescent cells showed increased numbers of mitochondria and higher levels of mitochondrial respiration, variable changes in mitochondrial DNA methylation, and elevated levels of humanin and MOTS-c. Humanin and MOTS-c administration modestly increased mitochondrial respiration and selected components of the SASP in doxorubicin-induced senescent cells partially via JAK pathway. Targeting metabolism in senescence cells is an important strategy to reduce SASP production for eliminating the deleterious effects of senescence. These results provide insight into the role of MDPs in mitochondrial energetics and the production of SASP components by senescent cells.

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“…Furthermore, accumulating evidence demonstrates that the senescence of NPCs, as induced by different forms of stress, plays a crucial role in the progression of IDD ( 4 ). As NPCs become senescent, their ability to proliferate is impeded and their functional capability is lost ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone 1‑34 inhibits senescence in rat nucleus pulposus cells by activating autophagy via the m‑TOR pathway

Wang

Jiao

et al. 2018

Mol Med Report

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Osteoporosis is closely associated with intervertebral disc degeneration. While parathyroid hormone (PTH) 1–34, which is an established drug used to treatosteoporosis, is thought to inhibit the disc degeneration associated with osteoporosis, the precise mechanism involved remains unclear. In the present study, primary Sprague-Dawley rat nucleus pulposus cells (NPCs) were cultured, phenotyped and then treated with dexamethasone (DXM) for 48 h. Cell area analysis and β-galactosidase staining were used to investigate the effect of DXM on the senescence of NPCs. In addition, the protein levels of LC3-II, Beclin-1, P62, p-mTOR and p-p70S6k were determined by western blotting and analyzing the regulatory effect of PTH upon autophagy and the mTOR signaling pathway in cells treated with DXM. Following autophagic inhibition induced by ATG5 siRNA transfection, the regulatory effect of PTH on senescence in NPCs were investigated in addition to the potential role of autophagy. As the concentration of DXM increased, the size of the NPCs was significantly enlarged and the proportion of cells with positive β-galactosidase staining increased significantly (P<0.05). In terms of protein expression, PTH treatment led to an increase in LC3-II and Beclin-1 proteins, a reduction in P62 protein, and inhibited p-mTOR and p-p70S6k protein expression in DXM-treated NPCs (P<0.05). PTH attenuated the effect of DXM according to the cell size and percentage of β-galactosidase-positive cells. However, the inhibition of autophagy via ATG5 siRNA transfection reversed the protective effect of PTH on cell senescence (P<0.05). Collectively, the present findings suggest that PTH may inhibit the senescence of NPCs induced by DXM by activating autophagy via the mTOR pathway.

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Rapamycin prevents the intervertebral disc degeneration via inhibiting differentiation and senescence of annulus fibrosus cells

Cited by 34 publications

References 41 publications

Subchondral bone microenvironment in osteoarthritis and pain

Subchondral bone microenvironment in osteoarthritis and pain

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Parathyroid hormone 1‑34 inhibits senescence in rat nucleus pulposus cells by activating autophagy via the m‑TOR pathway

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