Abstract
Osteoarthritis (OA) is a degenerative joint disease with multiple etiologies that affects individuals worldwide. No effective interventions are currently available to reverse the pathological process of OA. Sodium butyrate (NaB), a component of short-chain fatty acids (SCFAs), has multiple biological activities, including the attenuation of inflammation and anti-tumor activities in various diseases. However, whether the protective effects of NaB in OA are associated with the promotion of autophagy had not been investigated. Here, we explored the chondroprotective properties of NaB in an interleukin (IL)-1β-induced inflammatory chondrocyte model and an anterior cruciate ligament transection (ACLT) mouse model. Hematoxylin and eosin (HE), Safranin O, and immunohistochemical staining were performed to evaluate the effects of NaB treatment on articular cartilage. An optimal NaB dose for chondrocyte treatment was determined via cell counting kit-8 assays. Immunofluorescence and transmission electron microscopy were used to detect autophagy in chondrocytes. Flow cytometry was utilized to detect reactive oxygen species (ROS), cell cycle activity, and apoptosis in chondrocytes. Western blot and immunostaining were performed to evaluate the protein expression levels of relevant indicators. We found that the administration of NaB by oral gavage could attenuate cartilage degradation. In parallel, NaB treatment could enhance the activation of autophagy, increase autophagic flux, decrease extracellular matrix degradation, and reduce apoptosis by restraining inflammation, ROS production, and cell cycle arrest in IL-1β-treated chondrocytes. The protective effects of NaB could be partially abolished by the autophagy inhibitor 3-methyladenine (3-MA), which indicated that the protective effects of NaB against OA were partially governed by the enhancement of autophagy to restrain the formation of inflammatory mediators and ROS and regulate cell cycle progression and apoptosis in chondrocytes. In conclusion, NaB could attenuate OA progression by restoring impaired autophagy and autophagic flux via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, both in vitro and in vivo, implying that NaB could represent a novel therapeutic approach for OA.
Highlights
Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases among older individuals, causing serious social and economic burdens (Jones et al, 2019)
We investigated whether NaB could attenuate OA progression, including the amelioration of IL-1β-induced inflammation, reactive oxygen species (ROS) production, cell cycle arrest, and apoptosis, by restoring impaired autophagy via the phosphoinositide 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway in both an in vitro chondrocyte model and an in vivo mouse model of articular cartilage degeneration induced by anterior cruciate ligament transection (ACLT)
To the best of our knowledge, the present study is the first to demonstrate that NaB treatment can alleviate the IL-1β-induced inflammation, ROS, cell cycle arrest, and apoptosis in chondrocytes, an effect that appears to be mediated by the activation of autophagy flux in chondrocytes via the regulation of the PI3K/Akt/mTOR signaling pathway
Summary
Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases among older individuals, causing serious social and economic burdens (Jones et al, 2019). The incidence of OA has increased in association with the increased prevalence of obesity and the overall aging of the population. More than 28% of people over the age of 60 have been estimated to be affected by OA (Hunter and Bierma-Zeinstra, 2019), and the average cost per year associated with OA management has been estimated to account for 25–50% of a country’s GDP (PuigJunoy and Ruiz, 2015). Several etiologies have been verified to contribute to the risk of OA development, such as aging, obesity, and dysbiosis of the gut microbiota (GMB), no pharmacological therapy has yet been developed to alleviate the pathological processes underlying OA. The exploration of new medical therapies to alleviate, halt, or reverse OA development represents an urgent need
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