Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis

Takayama, Koji; Kawakami, Yoshiyuki; Kobayashi, Makoto; Greco, Nick; Cummins, James; Matsushita, Takehiko; Kuroda, R.; Kurosaka, Masahiro; Fu, Freddie H.; Huard, Johnny

doi:10.1186/s13075-014-0482-4

Cited by 157 publications

(173 citation statements)

References 42 publications

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“…Genetic ablation of cartilage mTOR (47) or inhibition of mTOR with the drug rapamycin (48,49) reduces the expression of catabolic enzymes and maintains cartilage viability in experimental OA. Here we establish that mTORC1 is activated early (within 24 h) in chondrocytes following a mechanical injury.…”

Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

121

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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

121

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“…Sirolimus inhibits the severity of cartilage degeneration and fibrosis in mouse models of OA and SSc, respec tively [152][153][154][155] ; however, the results of an early phase trial of sirolimus in patients with SSc showed adequate safety profiles, but were inconclusive 156 , and sirolimus is not currently being investigated for use in the treatment of OA or SSc. No published clinical trials have specifically addressed the safety of sirolimus in the treatment of OA, so further studies will be of great interest in determining whether sirolimus is capable of modulating pathologies associated with autophagy in this setting.…”

Section: Autophagy-modulating Therapiesmentioning

confidence: 92%

Autophagy: controlling cell fate in rheumatic diseases

2016

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Autophagy, an endogenous process necessary for the turnover of organelles, maintains cellular homeostasis and directs cell fate. Alterations to the regulation of autophagy contribute to the progression of various rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA) and systemic sclerosis (SSc). Implicit in the progression of these diseases are cell-type-specific responses to surrounding factors that alter autophagy: chondrocytes within articular cartilage show decreased autophagy in OA, leading to rapid cell death and cartilage degeneration; fibroblasts from patients with SSc have restricted autophagy, similar to that seen in aged dermal fibroblasts; fibroblast-like synoviocytes from RA joints show altered autophagy, which contributes to synovial hyperplasia; and dysregulation of autophagy in haematopoietic lineage cells alters their function and maturation in SLE. Various upstream mechanisms also contribute to these diseases by regulating autophagy as part of their signalling cascades. In this Review, we discuss the links between autophagy, immune responses, fibrosis and cellular fates as they relate to pathologies associated with rheumatic diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in rheumatic diseases.

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“…Based on current knowledge, autophagy, a self-protective mechanism in chondrocytes, has become a promising target to improve the viability and function of chondrocytes, thereby impeding the progress of OA [19, 20]. Autophagy may be activated in response to various stress stimuli, providing protective roles for chondrocytes [21].…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Vanilloid 5 Mediates Ca2+ Influx and Inhibits Chondrocyte Autophagy in a Rat Osteoarthritis Model

Wei¹,

Wang²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background: Autophagy, a self-protective mechanism of chondrocytes, has become a promising target to impede the progress of osteoarthritis (OA). Autophagy is regulated by cytosolic Ca²⁺ activity and may thus be modified by the Ca²⁺ permeable transient receptor potential channel vanilloid 5 (TRPV5). Therefore, we investigated the potential role of TRPV5 in mediating Ca²⁺ influx and in inhibiting chondrocyte autophagy in a rat OA model. Methods: The rat OA model was assessed by macroscopic and histological analyses. light chain 3B (LC3B) immunolocalization was detected by immunohistochemistry. TRPV5, LC3B and calmodulin in OA articular cartilage were assessed by real time polymerase chain reaction (RT-PCR) and western blotting. TRPV5 small interfering RNA (TRPV5 siRNA) were transfected into rat primary chondrocyte then the calmodulin and LC3B was detected by immunofluorescence. The functionality of the TRPV5 was assessed by Ca²⁺ influx. Western blot was used to measure autophagy-related proteins. Results: We constructed a monosodium iodoacetate (MIA) -induced rat OA model and found that ruthenium red (TRPV5 inhibitor) slowed the progression of joint destruction. We found that the TRPV5 and calmodulin were up-regulated but LC3B was down-regulated in articular cartilage following prolonged progression of OA. Furthermore, the up-regulated TRPV5 channel caused an increase in the Ca²⁺ influx in chondrocytes. The up-regulation of TRPV5 stimulated Ca²⁺ influx, which inhibited autophagy by increasing the production of calmodulin, phosphorylation of calmodulin dependent protein kinases II (p-CAMK II), phosphorylation of Beclin1 (p-Beclin1), and protein of B-cell lymphoma-2 (Bcl-2), and attenuating ratio of LC3-II/ LC3-. Conclusion: Up-regulated TRPV5 as an initiating factor inhibited chondrocyte autophagy via the mediation of Ca²⁺ influx.

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Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis

Cited by 157 publications

References 42 publications

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Autophagy: controlling cell fate in rheumatic diseases

Transient Receptor Potential Vanilloid 5 Mediates Ca2+ Influx and Inhibits Chondrocyte Autophagy in a Rat Osteoarthritis Model

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