Shikonin, a promising therapeutic drug for osteoarthritis that acts via autophagy activation

Wang, Anquan; Fang, Sheng; Lu, Ming; Zhou, Hongxiang; Huang, Wei; Li, Lei; Gao, Weilu; Yin, Zongsheng

doi:10.1016/j.intimp.2022.108563

Cited by 12 publications

(3 citation statements)

References 42 publications

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“…Our previous studies have demonstrated that ECM degradation can be improved by activating autophagy in OA chondrocytes ( Huang et al, 2020 ; Wang et al, 2022 ). Next, we conducted an in-depth study of the mechanism by which DIM inhibits LPS-induced chondrocyte apoptosis in vitro .…”

Section: Discussionmentioning

confidence: 99%

3,3′-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

Tang

Qin²,

Wang³

et al. 2022

Front. Pharmacol.

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Osteoarthritis (OA) is a chronic degenerative joint disease characterized by articular cartilage destruction. The pathological mechanisms are complex; in particular, inflammation, autophagy, and apoptosis are often involved. 3,3-Diindolylmethane (DIM), a phytoconstituent extracted from cruciferous vegetables, has various effects such as anti-inflammatory, antioxidant and anti-apoptotic. However, the effects of DIM on osteoarthritic chondrocytes remain undetermined. In this study, we simulated a lipopolysaccharide (LPS)-induced osteoarthritis model in human primary chondrocytes. We found that LPS stimulation significantly inhibited autophagy, induced chondrocyte apoptosis and extracellular matrix (ECM) degradation, which could be ameliorated by DIM. DIM inhibited the expression of a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), matrix metalloproteinase 13 (MMP13), cleaved caspase-3, Bax, and p62, and increased the expression level of collagen II, aggrecan, Bcl-2, light chain 3 Ⅱ (LC3 Ⅱ), and beclin-1. Mechanistic studies showed that DIM increased chondrocyte autophagy levels by inhibiting the activation of PI3K/AKT/mTOR pathway. In mice destabilization of the medial meniscus (DMM) model, immunohistochemical analysis showed that DIM inhibited the expression of p-PI3K and cleaved caspase-3, increased the expression of LC3 Ⅱ. Furthermore, DIM relieved joint cartilage degeneration. In conclusion, our findings demonstrate for the first time that DIM inhibits LPS-induced chondrocyte apoptosis and ECM degradation by regulating the PI3K/AKT/mTOR-autophagy axis and delays OA progression in vivo.

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Section: Discussionmentioning

confidence: 99%

3,3′-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

Tang

Qin²,

Wang³

et al. 2022

Front. Pharmacol.

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“… [ 147 ] Resveratrol Rat tibial defect model BMSCs, Osteoblasts Stimulation of autophagy drives BMSC survival, osteogenesis, and angiogenesis. [ 148 ] Shikonin OA cell model Chondrocytes Promote chondrocyte anabolism [ 149 ] Sulforaphane Mouse calvarial model Osteoclasts Reduce the number of autophagosomes and inhibit autophagy activation of osteoclasts from reducing osteoclast formation [ 150 ] Ursolic acid Rat Ovariectomy model Osteoclasts Block osteoclast autophagy and reduce the expression of FOS and NFATC1 [ 62 ] …”

Section: Therapeutic Approaches For Bone Diseases By Modulating Autop...mentioning

confidence: 99%

The role of autophagy in bone metabolism and clinical significance

et al. 2023

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The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material’s properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future. Abbreviations: Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1β: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberou...

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“…In an interleukin (IL)-1β-induced cellular model of osteoarthritis, purslane treatment reduced the mRNA and protein levels of thrombospondin motif-5, the disintegrin of the matrix metalloproteinase-1, and metalloproteinases. In addition, after analysis using the Osteoarthritis Research Society International (OARSI) score, it was found that the symptoms of cartilage degeneration were reduced after Shikonin treatment in mice [15]. In sepsis, Shikonin improved sepsis-induced lung injury by modulating the miRNA-140-5p/toll-like receptor-4 (TLR4) pathway [16].…”

Section: Anti-inflammatorymentioning

confidence: 99%

Pharmacological Effects of Shikonin and Its Potential in Skin Repair: A Review

Song,

Ding,

Hao

et al. 2023

Molecules

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Currently, skin injuries have a serious impact on people’s lives and socio-economic stress. Shikonin, a naphthoquinone compound derived from the root of the traditional Chinese medicine Shikonin, has favorable biological activities such as anti-inflammatory, antibacterial, immunomodulatory, anticancer, and wound-healing-promoting pharmacological activities. It has been reported that Shikonin can be used for repairing skin diseases due to its wide range of pharmacological effects. Moreover, the antimicrobial activity of Shikonin can play a great role in food and can also reduce the number of pathogenic bacteria in food. This paper summarizes the research on the pharmacological effects of Shikonin in recent years, as well as research on the mechanism of action of Shikonin in the treatment of certain skin diseases, to provide certain theoretical references for the clinical application of Shikonin, and also to provides research ideas for the investigation of the mechanism of action of Shikonin in other skin diseases.

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Shikonin, a promising therapeutic drug for osteoarthritis that acts via autophagy activation

Cited by 12 publications

References 42 publications

3,3′-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

3,3′-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy

The role of autophagy in bone metabolism and clinical significance

Pharmacological Effects of Shikonin and Its Potential in Skin Repair: A Review

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