Active vitamin D activates chondrocyte autophagy to reduce osteoarthritis via mediating the AMPK–mTOR signaling pathway

Abstract

Osteoarthritis (OA) is a common joint degenerative disease. Vitamin D (VD) is essential for bone health. We hypothesized that active VD could be used as a therapeutic treatment for OA. Low serum levels of 25-hydroxyvitamin D [25(OH)D] have been found in patients with OA, and thus the serum level of VD could be diagnostic of OA. To test this, we established a mouse model of OA. The results from staining with hematoxylin–eosin and Safranin O – Fast Green indicated that active VD reduced the symptoms of OA in mice. The results from Western blotting indicated that treatment with VD increased the activity of the p-AMPK–AMPK signaling pathway and decreased the p-mTOR–mTOR pathway; it also increased the ratio of LC3II:LC3I antibodies and the protein expression levels of Beclin-1, but decreased the level of p62. Further, treatment with VD reduced the levels of tumor necrosis factor-α and interleukin-6 both in cartilage tissues and in chondrocytes. Administration of the AMPK inhibitor compound C and autophagy inhibitor 3-methyladenine (3-MA) reversed these changes following VD treatment. In addition, the results from transfection with mRFP-GFP-LC3 indicated that active VD led to autophagosome aggregation in OA chondrocytes. 3-MA inhibited cell autophagy and promoted inflammation in OA. This study provides evidence that active VD activate chondrocyte autophagy to reduce OA inflammation via activating the AMPK–mTOR signaling pathway. Treatment with active VD could be a novel therapeutic option for OA.

The role of autophagy in bone homeostasis

“…Vitamin D is essential for bone mineral homeostasis and can promote bone metabolism by stimulating OB and OC differentiation (Kogawa et al, 2010; (Ji et al, 2019). Furthermore, it has been found that active vitamin D activated chondrocyte autophagy to reduce osteoarthritis via mediating the AMPK-mTOR signaling pathway (Kong et al, 2020).…”

“…This dual regulatory effect of 1α,25(OH)2D3 on osteoclast autophagy suggests that some drugs targeting autophagy may serve as an effective to 1α,25(OH)2D3 in the treatment of osteoporosis (Ji et al, 2019). Furthermore, it has been found that active vitamin D activated chondrocyte autophagy to reduce osteoarthritis via mediating the AMPK‐mTOR signaling pathway (Kong et al, 2020).…”

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

“…Several groups illustrated thaactivationt of AMPK phosphorylation leads to suppressing NF-κB and its downstream molecule p65, which is involved in modulating OA cartilage in response to IL-1β–induced inflammation ( Yang et al, 2019 ; Wang et al, 2020a ; Zhu et al, 2020 ). Kong et al (2020) suggest that AMPK-mTOR signaling pathway could reduce OA inflammation via activation of chondrocyte autophagy in the presence of active vitamin D. Several investigators at this time also observed the effect of metformin and resveratrol in the treatment of OA. Wei et al (2018) showed that resveratrol suppresses induction of pAMPK and SIRT1 protein expression in OA rats.…”

Osteoarthritis year in review 2020: biology

“…AMPK activity can directly stimulate J o u r n a l P r e -p r o o fautophagy by stimulating ULK3 activity and indirectly via the inhibition of mTORC1. In line with previous years, various research groups have published work in which they aimed to increase autophagy in order to slow down the progression of OA[41][42][43].…”