Abstract
Currently there is no effective treatment available for osteoarthritis (OA). We have recently developed Kyoto University Substances (KUSs), ATPase inhibitors specific for valosin-containing protein (VCP), as a novel class of medicine for cellular protection. KUSs suppressed intracellular ATP depletion, endoplasmic reticulum (ER) stress, and cell death. In this study, we investigated the effects of KUS121 on chondrocyte cell death. In cultured chondrocytes differentiated from ATDC5 cells, KUS121 suppressed the decline in ATP levels and apoptotic cell death under stress conditions induced by TNFα. KUS121 ameliorated TNFα-induced reduction of gene expression in chondrocytes, such as Sox9 and Col2α. KUS121 also suppressed ER stress and cell death in chondrocytes under tunicamycin load. Furthermore, intraperitoneal administration of KUS121 in vivo suppressed chondrocyte loss and proteoglycan reduction in knee joints of a monosodium iodoacetate-induced OA rat model. Moreover, intra-articular administration of KUS121 more prominently reduced the apoptosis of the affected chondrocytes. These results demonstrate that KUS121 protects chondrocytes from stress-induced cell death in vitro and in vivo, and indicate that KUS121 is a promising novel therapeutic agent to prevent the progression of OA.
Highlights
There is no effective treatment available for osteoarthritis (OA)
KUS121 suppresses TNF‐α mediated apoptosis in chondrocytes differentiated from ATDC5 cells
Col2a and Sox[9] mRNA expression, expressed in differentiated chondrocytes[21,22], was reduced in TNF-α treated cells, and restored by the addition of KUS121 (Fig. 1D,E). These results demonstrated that KUS121 protected chondrocytes from TNF-α-induced cell damage
Summary
There is no effective treatment available for osteoarthritis (OA). We have recently developed Kyoto University Substances (KUSs), ATPase inhibitors specific for valosin-containing protein (VCP), as a novel class of medicine for cellular protection. Intra-articular administration of KUS121 more prominently reduced the apoptosis of the affected chondrocytes These results demonstrate that KUS121 protects chondrocytes from stress-induced cell death in vitro and in vivo, and indicate that KUS121 is a promising novel therapeutic agent to prevent the progression of OA. We observed that the loss-of-function of ter[94] (Drosophila VCP) mitigates neurodegeneration in a Drosophila model of polyglutamine diseases, and developed new chemical compounds that inhibit the ATPase activity but not the other cellular functions of VCP We named these compounds “Kyoto University Substances (KUSs)” or “VCP modulators”[13]. KUS121 exerts potent protective effects on retinal neuronal cells, including retinal ganglion cells and photoreceptors, dopaminergic neurons in the midbrain, cardio-muscles, and cerebral neurons, in animal models of different diseases[14,15,16,17] These protective effects are profoundly coupled with their ability to ameliorate decreased ATP levels and ER stress in the cells. The link between ER stress and chondrocyte cell death, as well as the effects of KUS121 on these phenomena in vitro and in vivo in monosodium iodoacetate (MIA)-induced rat OA m odels[19,20]
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