Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis

Zhang, Minjie; Mani, Sriniwasan B.; He, Yao; Hall, Amber M.; Xu, Lin; Li, Yefu; Zurakowski, David; Jay, Gregory D.; Warman, Matthew L.

doi:10.1172/jci83676

Cited by 79 publications

(75 citation statements)

References 46 publications

(56 reference statements)

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“…A recent study analysed the causal relationship between chondrocytes death and cartilage damage using confocal microscopy, standard histology, genetically engineered mice, and DMM surgery [124]. Authors showed that mice whose chondrocytes had been killed (i.e., Diphteria Toxin A (DTA)-ablated) before DMM surgery had significantly less cartilage damage than control mice.…”

Section: Apoptosis In Chondrocytes and Osteoarthritis (Oa) Developmentioning

confidence: 99%

“…Authors showed that mice whose chondrocytes had been killed (i.e., Diphteria Toxin A (DTA)-ablated) before DMM surgery had significantly less cartilage damage than control mice. Although DMM surgery causes ultimately chondrocytes death, it is the dysfunction of living chondrocytes (i.e., their catabolic phenotype), not their death, that enhances cartilage damage following injury [124]. …”

Section: Apoptosis In Chondrocytes and Osteoarthritis (Oa) Developmentioning

confidence: 99%

“…Also, therapies dedicated to the reduction of the catabolic phenotype of chondrocytes may protect against post traumatic OA [124]. …”

Section: Targeting Chondrocyte Apoptosis For Oa Treatmentmentioning

confidence: 99%

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Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

266

220

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Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.

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Section: Apoptosis In Chondrocytes and Osteoarthritis (Oa) Developmentioning

confidence: 99%

Section: Apoptosis In Chondrocytes and Osteoarthritis (Oa) Developmentioning

confidence: 99%

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Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

266

220

View full text Add to dashboard Cite

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“…The intra-articular administration of caspase inhibitors has been shown to inhibit chondrocyte death and cartilage degradation in OA rabbit models [46,47]. In contrast, a recent study using a 3D confocal cartilage imaging technique showed that chondrocyte death by diphtheria toxin did not result in cartilage damage [48]. Therefore, it currently remains controversial whether chondrocyte death itself causes cartilage degradation.…”

Section: Chondrocyte Deathmentioning

confidence: 99%

“…Chondrocyte apoptosis or autophagic death also increases DAMPs because both result in secondary necrosis [33]. However, the significance of the DAMPs released from necrotic chondrocytes still needs to be investigated because the ablation of chondrocytes by diphtheria toxin prior to the operation for surgical OA reduces cartilage damage [48]. In this case, DAMPs must be considered to have already been released from necrotic chondrocytes and cartilage may contain no sufficient DAMPs when mechanical injury occurs.…”

Section: Chondrocyte Deathmentioning

confidence: 99%

Cell Death in Chondrocytes, Osteoblasts, and Osteocytes

Komori

2016

IJMS

144

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Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt–FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced.

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Intra‐articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis

Dhanabalan

Dravid

Agarwal

et al. 2022

Bioengineering & Transla Med

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Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease‐modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin‐loaded in poly(lactic‐co‐glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra‐articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery‐induced OA when administered as a prophylactic or therapeutic regimen. Together, the study demonstrates the feasibility of using RMPs as a potential clinically translatable therapy to prevent the progression of post‐traumatic OA.

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Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis

Cited by 79 publications

References 46 publications

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Cell Death in Chondrocytes, Osteoblasts, and Osteocytes

Intra‐articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis

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