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Osteoarthritis (OA) is a common degenerative joint disease and is a leading cause of disability and reduced quality of life worldwide. There are currently no clinical treatments that can stop or slow down OA. Drugs have pain-relieving effects, but they do not slow down the course of OA and their long-term use can lead to serious side effects. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Autophagy is an intracellular protective mechanism, and targeting autophagy-related pathways has been found to prevent and treat various diseases. Attenuation of the autophagic pathway has now been found to disrupt cartilage homeostasis and plays an important role in the development of OA. Therefore, modulation of autophagic signaling pathways mediating cartilage homeostasis has been considered as a potential therapeutic option for OA. Phytochemicals are active ingredients from plants that have recently been found to reduce inflammatory factor levels in cartilage as well as attenuate chondrocyte apoptosis by modulating autophagy-related signaling pathways, which are not only widely available but also have the potential to alleviate the symptoms of OA. We reviewed preclinical studies and clinical studies of phytochemicals mediating autophagy to regulate cartilage homeostasis for the treatment of OA. The results suggest that phytochemicals derived from plant extracts can target relevant autophagic pathways as complementary and alternative agents for the treatment of OA if subjected to rigorous clinical trials and pharmacological tests.
Osteoarthritis (OA) is a common degenerative joint disease occurring in the elderly population and is the most common cause of pain and disability worldwide. Its pathology is characterized by progressive cartilage degeneration, increased subchondral bone remodeling and bone redundancy formation (
Conservative treatment is currently the main treatment for OA and is mainly limited to pain control. Various drugs, such as Nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, glucosamine, steroids, and hyaluronic acid (
Autophagy is a self-protective mechanism (
Recently, relevant studies have found that phytochemicals play an important role in disease prevention and treatment by mediating the autophagic pathway (
Phytochemicals improve cartilage homeostasis via mediated autophagy against OA
Phytochemical | Plant species, family | Model | Dosage range | Active concentration | Signal pathways/Mechanisms | References | |
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Polyphenols | Curcumin |
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5 μM, 10 μM, 15 μM, and 20 μM | 10 μM | MAPK/ERK1/2 signal pathway |
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1.25–20 μM | 10 μM | — |
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50 mg/kg |
50 mg/kg | AKT/mTOR pathway |
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10 μM | 10 μM | |||||
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200 μg/kg body weight and 400 μg/kg body weight |
200 μg/kg body weight | E2F1/PITX1 pathway and AKT/mTOR pathway |
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Hydroxytyrosol |
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0, 12.5, 25, 50, 100, 200 and 400 μM, last for 24 h | 50 μM | SIRT6 pathway |
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100 μM for 30 min | 100 μM | SIRT1 pathway |
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Resveratrol |
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125 mg |
125 mg | HIF-1 |
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Butein |
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0.6 μg/ml-10 μg/ml (or 2.25–36 μM) for 24 h | 10 μg/ml (36 μM) | AMPK/TSC2/ULK1/mTOR pathway |
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Mangiferin |
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10 mg/kg once a day for 8 weeks | 10 mg/kg | AMPK signaling pathway |
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0, 5, 10, 50, 100, 200 μM | 100 μM | |||||
Delphinidin |
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10–75 μM | 40 μM | Nrf2 and NF-κB were activated |
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Punicalagin |
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0–50 μg/ml | 50 μg/ml | Autophagic flux in chondrocytes after TBHP treatment recovered |
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20 mg/kg via oral administration each day for 8 weeks | 20 mg/kg | |||||
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0, 25, 50 and 100 μM | 50 μM | Foxo1/Prg4/HIF3 |
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10 mg/kg |
10 mg/kg | |||||
(-)Epigallocatechin 3-Gallate |
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10 μM EGCG by intra-articular injection once every 3 days for 5 weeks | 10 μM | mTOR expression was reduced and LC3, Beclin-1 and p62 expression were increased |
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Chlorogenic acid |
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0, 50, 100, 200, 250, 400 μM | 250 μM | Antioxidant response proteins Nrf2 and NF-κB were increased |
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Flavonoids | Icariin |
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0, 3, 5, 7, 10, and 20 μM | 10 μM | p65 nuclear translocation and IκBα protein degradation were inhibited |
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20, 40, or 80 mg/kg/day by intraperitoneal injection for 4 consecutive weeks | 20 mg/kg | PI3K/AKT/mTOR pathway |
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1–100 μM | 80 μM | |||||
Baicalin |
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20 μM | 20 μM | miR-766–3p level was upregulated and AIFM1 expression was decreased |
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Glabridin |
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0.01–10 μM | 1 μM | mTOR pathway |
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1, 5, and 10 mg/kg for 4 or 8 weeks | 1 mg/kg | |||||
Rhoifolin |
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0, 5, 10, and 20 μM | 20 μM | P38/JNK pathway and PI3K/AKT/mTOR pathway |
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20 μM intra-articular injection weekly for 8 weeks | 20 μM | |||||
Eupatilin |
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0, 25, 50, 100 μM | 25 μM | Senstrin2-dependent autophagy |
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Sinensetin |
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0, 10, 20, 30, 40, and 50 μM | 10 μM | AMPK/mTOR signaling pathway |
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50 mg/kg by gavage for 8 w | 50 mg/kg | |||||
Terpenoids | Morroniside |
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0, 1, 20, 200 μM | 20 μM | PI3K/AKT/mTOR signal pathway |
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Lycopene |
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0.001–10 μM | 0.1 μM | MAPK and PI3K/Akt/NF-κB axis |
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Celastrol |
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0–1.6 μM | 0.2 μM | The expression of LC3-II and Beclin-1 increased |
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0.5 mg/kg, 1 mg/kg by intraperitoneal injection for 12 w | 0.5 mg/kg | |||||
Coumarins | Isoimperatorin |
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500 mg/kg |
500 mg/kg | mTORC1 pathway |
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1–100 mM | 1 μM | |||||
Isopsoralen |
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5, 10, 20, and 40 μg/ml | 20 μg/ml | LC3-II and LAMP-1 expression was significantly increased, but p62/SQSTM1 expression was significantly decreased |
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Saponin | Astragaloside IV |
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50 μg/ml | 50 μg/ml | Protein expression of LC3-II/I was increased and that of P62/SQSTM1 was decreased |
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Huzhangoside D |
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17, 34, 68 mg/kg |
17 mg/kg | AKT and mTOR signaling pathway |
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Small molecules compounds |
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0.6 mg/kg, 0.8 mg/kg, and 1 mg/kg |
0.6 mg/kg | PI3K/AKT/MTOR signal pathway |
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10, 20, 40 μM | 10 μM | |||||
Dihydroartemisinin |
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0–10 μM | 1 μM | LC3-II and ATG5 levels were increased and the expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1 was decreased. p65 and IκBα protein nuclear translocation and degradation were impaired |
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Shikimic Acid |
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0, 0.1,1,5,10, and 20 mM | 0.1 mM | MAPK pathway |
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20 mM in 100 μL |
20 mM | |||||
Sinomenium |
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10 mM | 10 mM | AMPK/mTOR signaling pathway |
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5 mg/kg |
5 mg/kg | |||||
Tetrahydrohyperforin |
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6 g/kg |
6 g/kg | The levels of LC3-II, Beclin-1 and Atg5 were increased and The level of |
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50, 100, 150 and 200 μmol/L | 50 μmol/L |
Chondrocytes are the most dominant cells in cartilage tissue and play an important role in maintaining matrix integrity, and abnormal chondrocyte function is closely related to the development of OA. Chondrocytes play an important role in maintaining cartilage metabolic homeostasis by maintaining the stability of cartilage tissue and ECM (
Autophagy is an evolutionarily highly conserved degradation system that relies on the degradation of dysfunctional organelles and biomolecules by lysosomes under the regulation of autophagy-associated genes (ATG) to remove protein aggregates and dysfunctional organelles to maintain cellular homeostasis and protect cells from apoptosis (
Activation of autophagy against osteoarthritis by maintaining cartilage homeostasis. Produced using Servier Medical Art (
Phytochemicals from traditional medicinal plants are inexpensive and widely available, and can exert anti-inflammatory and antioxidant effects with good pharmacological activity. In recent years, various phytochemicals have been used in the prevention and treatment of various diseases by modulating autophagic targets, such as cardiovascular diseases and cancer (
Autophagy pathways of phytochemicals in anti-osteoarthritis.
Polyphenols, a large family of naturally occurring organic compounds characterized by multiples of phenol units, are widely distributed in numerous plants including vegetables, fruits, and botanical drugs (
Curcumin, a polyphenol derived from
Olive oil is the main source of fat in the Mediterranean diet (
Resveratrol (RSV), an active substance derived from
Butein is a polyphenol derived primarily from
Mangiferin, a natural polyphenol derived mainly from
The natural compound anthocyanins extracted from
Punicalagin (PUG) is a hydrolyzable polyphenol extracted from
(-)-Epigallocatechin gallate (EGCG) is the most abundant bioactive polyphenol in
Chlorogenic acid (CGA) is a natural polyphenolic compound from
In recent years, researches have confirmed the beneficial effects of flavonoids to health, including their use in conditions related to autophagy, such as neurodegenerative diseases (
Icariin, a flavonoid compound extracted from
Baicalin, a principal flavonoid extracted from roots of
Glabridin is a flavonoid derived from
Rhoifolin (ROF) is a flavanone derived from
Eupatilin is a flavonoid derived from
Sinensetin is a polymethoxylated flavonoid derived from
Terpenoids are the largest class of natural products, most of which are of plant origin, and their biological properties, mainly anti-proliferative and apoptotic, have been shown to play an important role in cancer prevention and health promotion through the promotion of autophagy (
Lycopene (LYC), a lipid-soluble carotenoid naturally found in
Celastrol is a natural triterpenoid found in traditional Chinese medicine botanical drugs
Coumarins are different species of plant-derived secondary metabolites that have anti-inflammatory and anti-apoptotic properties and have recently been found to treat cancer by mediating autophagy (
Isoimperatorin is an linear furanocoumarin isolated from the
Isopsoralen is a linear furanocoumarin isolated from the fruit of
Saponins originating from different plants have also been found to exert anti-inflammatory and antioxidant activity through the mediation of autophagy and thus be used in the treatment of various diseases (
Astragaloside IV (AST) is a unique active saponin compound extracted from
Huzhangoside D is a saponin isolated from
In addition to the above phytochemicals, a number of small-molecule chemicals derived from plants, such as various natural compounds and compound analogues, have also been found to enhance autophagy to treat various diseases (
Dihydroartemisinin (DHA), a semisynthetic derivative of Artemisinin (ART), has fewer side effects than ART, the main phytochemical extracted from
Shikimic acid (SA) is a hydroaromatic compound extracted from
Sinomenium (SIN) is a natural alkaloid extracted from the medicinal plant
Tetrahydrohyperforin (IDN5706) is a tetrahydro derivative of hyperforin, one of the main active components of
In the development of OA, the activation of autophagy has positive significance for the survival of chondrocytes, and autophagy as a therapeutic target for OA has a broad clinical application prospect. Targeted application of drugs to regulate chondrocyte autophagy levels is expected to provide more options for the clinical treatment of OA. In recent years, plant extracts and phytochemicals isolated from the former have gradually gained popularity and attracted widespread attention. They have definite anti-osteoarthritic ability, which is mainly achieved by mediating relevant autophagy-related pathways, and improving chondrocyte autophagy. Given the cost-effectiveness and wide availability of phytochemicals, and the growing awareness of their role in promoting chondrocyte autophagy and thus treating OA, research on improving OA is rapidly increasing. Phytochemicals emerge as an important source for the development of novel OA therapeutics, providing a valuable source of OA therapeutics, lead compounds or adjuvants for the discovery of new drugs that exert multifaceted biological activities in maintaining human health and preventing disease. However, except from curcumin and RSV (
MS and XZ conceptualized the review. ZT drafted the manuscript, drew illustrations of autophagy-related pathways and processed them at the same time. MS and XZ revised and supplemented the manuscript. All the authors participated in writing and giving feedback on the manuscript. All authors have read and approved the final manuscript.
This work was supported by the Scientific research funding project of the Department of Education of Liaoning Province (LJC2019ST02), 2019 Outstanding Talents Support Plan for Higher Education Institutions in Liaoning Province (WR2019024) and the Scientific research funding project of the Department of Education of Liaoning Province (LJKZ1048).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.