Table 1.

Effects of the pharmacological agents manipulating autophagy on human chondrocytes.

Study	Reagents	Condition of Subject’s Cartilage	Act of Reagents in Autophagy	Role of Reagents in Osteoarthritis	Related Mechanisms
Ribeiro et al. [22]	Insulin	OA human chondrocyte	Inhibition	Induction	Autophagy via Akt/mTOR signaling pathway. Activation of inflammation (loss of proteoglycans, increased MMP-13 and IL-1β).
Hwang et al. [23]	Monosodium urate (MSU)	OA human chondrocyte	Activation	Induction	Autophagy via Akt/mTOR signaling pathway. Independent of other cell death mechanisms, including apoptosis, ER stress-induced death, necroptosis, and pyroptosis.
Shen et al. [24]	Oxidized low density lipoprotein (Ox-LDL)	OA human chondrocyte	Activation	Induction	Increased ox-LDL and lectin-like ox-LDL receptor-1 (LOX-1) expression level was found in OA patients. Tumor necrosis factor-α mediated chondrocyte death.
Li et al. [25]	Plant homeodomain finger protein 23 (PHF 23)	OA human chondrocyte	Inhibition	Induction	Expression of PHF 23 increased in OA and was induced by IL-1β through inflammatory stress. PHF 23 suppressed autophagy of chondrocytes and accelerated apoptosis.
Wangyang et al. [26]	P63	OA human chondrocyte	Inhibition	Induction	P63 was overexpressed in OA patients. P63 upregulation correlated with suppressed autophagy and cell viability.
Sekar et al. [27]	Saturated fatty acid (palmitic acid (PA), stearic acid (SA), lauric acid (LA), myristic acid (MA))	OA human chondrocyte	PA, SA, MA: Autophagy activation LA: Similar to control	PA, SA, MA: OA inductionLA: Similar to control	Autophagy via NF-κB signaling pathway. PA, SA, MA treatment significantly decreased early chondrogenic markers such as ACAN, COL2, and SOX9 and significantly increased degenerative markers such as MMP13, ADAMTS4, and ADAMTS5. LA showed similar expressions in comparison with the controls.
Lee et al. [10]	Delphinidin	Normal human chondrocytes cell line (C28/I2),	Activation	Prevention	Delphinidin inhibited oxidative stress-induced apoptosis while it activated autophagy via NF-κB and Nrf2 pathways.
Duan et al. [28]	AdipoRon	OA human chondrocyte	Activation	Prevention	AdipoRon significantly alleviates the calcification of OA chondrocytes via activating AMPK/mTOR signaling to promote autophagy.
Xiao et al. [29]	Morroniside	OA human chondrocyte	Inhibition	Prevention	Morroniside inhibited chondrocyte autophagy through PI3K/AKT/mTOR signaling, thus it prevented cell death. Overexpression of autophagy enhanced the protection of Morroniside on chondrocytes.
Khan et al. [30]	Sucrose	OA human chondrocyte	Activation	Prevention	Sucrose induced autophagy in vitro dependent on the activation of AKT/mTOR/P70S6K signaling pathway and independent of ROS. Sucrose activated autophagy blocked IL-1β induced apoptosis and mRNA expression of MMP-13, COX-2, PGE-2, and IL-6.
Wang et al. [20]	Advanced glycation end products (AGEs)	Normal human chondrocyte	Biphasic effects	Biphasic effects	Low doses of AGEs over a short amount of time stimulated chondrocyte proliferation and autophagy by limiting phosphorylation of Akt/mTOR signaling. High dose and long exposure to AGEs inhibited cell viability and autophagy by increasing phosphorylation of Akt/mTOR signaling. AGEs can downregulate PPARG and that PPARG maintains cell viability by activating the Akt/mTOR signaling pathway as well as inducing autophagy.
Carames et al. [31]	Glucosamine	Normal human chondrocyte	Activation	Prevention	Glucosamine is an effective autophagy activator, and the enhancement of autophagy was mainly dependent on the Akt/FOXO and mTOR pathway.
Ansari et al. [32]	Butein	OA human chondrocyte	Activation	Prevention	Butein increased the phosphorylation of AMPKαThr-172, TSCSer-1387, and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448. Increased autophagy flux that correlated with the suppression of the IL-1β mediated expression of IL-6.
Liu et al. [33]	Astragaloside Ⅳ (AST)	OA human chondrocyte	Activation	Prevention	AST-mediated autophagy protected against chondrocyte apoptosis induced by IL-1β.
Moussa et al. [34]	Platelet rich plasma (PRP)	OA human chondrocyte	Activation	Prevention	PRP increased significantly the proliferation of chondrocytes, decreased apoptosis and increased autophagy via FOXO1, FOXO3, HIF-1. PRP caused a significant decrease in MMP3, MMP13, ADAMTS-5, IL-6, and COX-2 while increasing TGF-β, aggrecan, collagen type 2, TIMPs and intracellular IL-4, IL-10, IL-13.
Nogueira-Recalde et al. [35]	Fenofibrate (FN)	OA and ageing human chondrocyte	Activation	Prevention	FN (PPARα agonist) reduced proteoglycan loss and protected against cartilage degradation. PPARα was mainly expressed in the superficial zone in non-OA cartilage with decreased expression in OA patients. FN reduced both senescence and inflammation and increased autophagy in both aging human and OA chondrocytes.
Cetrullo et al. [36]	Hydroxytyrosol (HT)	Normal human chondrocytes cell line (C28/I2), OA human chondrocyte	Activation	Prevention	The protective effect requires the deacetylase sirtuin 1 (SIRT-1) and silencing of this enzyme prevented HT from promoting the autophagic process and cell survival. HT supports autophagy even in a SIRT-1-independent manner, by increasing p62 transcription, required for autophagic degradation of polyubiquitin-containing bodies. HT exerts its cell protective action in C28/I2 line and human OA chondrocytes by the same modalities.
Ansari et al. [37]	Butea monosperma (Butein, BME)	OA human chondrocyte	Activation	Prevention	BME activated autophagy via inhibition of mTOR pathway. BME suppressed the IL-1β induced expression of IL-6, MMP-3, MMP-9, and MMP-13.
Yu et al. [38]	T-2, HT-2 toxin	Normal human chondrocytes cell line (C28/I2)	Activation	Prevention	T-2 and HT-2 toxins induce apoptosis and autophagy, and the level of oxidative stress plays an important role in autophagy activation. The expression levels of apoptosis and autophagy induced by T-2 toxin were significantly higher when compared with those levels induced by the HT-2 toxin. The activation of autophagy can reduce oxidative damage and apoptosis.
Liao et al. [39]	Resveratrol (Sirt I inducer)	OA human chondrocyte	High levels of Sirt I inhibited autophagy in OA	Prevention	Sirt I regulates autophagy by interacting with Atg7. The expression of Sirt I might be age-related: it is high in young people and decreased in elderly and OA patients. Of note, the high levels of Sirt I reduced autophagy in OA. Through increasing the activity of Sirt I the autophagic cell death of OA chondrocyte could be inhibited.
Zhong et al. [40]	miRNA-335-5p	OA human chondrocyte	Activation	Prevention	The expression of miRNA-355-5p was significantly lower in OA chondrocytes. miRNA-355-5p can significantly alleviate inflammation in human OA chondrocytes by activating autophagy.
Wang et al. [41]	miR-140-5p/miR-149	OA human chondrocyte	Activation	Prevention	The overexpression of miR-140-5p/miR-149 inhibited apoptosis and promoted proliferation and autophagy of primary human chondrocytes via downregulating FUT1.
D’Adamo et al. [42]	miRNA-155	Normal human chondrocyte and cell line (T/C28a2)	Inhibition	Induction	miRNA-155 regulates autophagy by suppressing MAP1LC3, GABARAPL1, Atg3, Atg5, Atg, 14, ULK1, and FOXO3.miRNA-155 inhibited autophagy by activating mTOR pathway.
Yang et al. [43]	miRNA-411	OA induced C28/I2 chondrocyte cell line by IL-1β	Mimic: inhibition, Inhibitor: activation	Mimic: prevention, Inhibitor: induction	miRNA-411 regulates autophagy by targeting HIF-1α. miRNA-411 mimic inhibited autophagy by reducing HIF-1α while miRNA-411 inhibitor activated autophagy by increasing HIF-1α in chondrocytes. miRNA-411 was downregulated in OA chondrocyte, so this causes activation of autophagy by increasing HIF-1α. Thus, downregulated miRNA-411 is closely associated with the development of OA.
Tian et al. [44]	upregulated small nuclear RNA host gene 7 (SNHG7), downregulated miR-34a-5p	OA human chondrocyte	Inhibition	Prevention	SNHG7 and SYVN1 were downregulated, but miR-34a-5p was upregulated in OA. Upregulated SNHG7 promoted cell proliferation as well as inhibited cell apoptosis and autophagy by sponging miR-34a-5p through regulating SYNV1 in OA cells.
Yang et al. [45]	Long non-coding RNA reprogramming (lncRNA-ROR)	OA human chondrocyte	Activation	Prevention	Level of lncRNA-ROR was decreased in OA. Overexpression of lncRNA-ROR dramatically promoted cell viability of OA chondrocytes. Knockdown lncRNA-ROR inhibited apoptosis and promoted autophagy by regulating HIF-1α and p53.
Akasaki et al. [46]	Downregulated FOXO transcription factors	OA human chondrocyte	Inhibition	Induction	Reduced expression of FOXO transcription factors in chondrocytes increased susceptibility to cell death induced by oxidative stress. This was associated with reduced antioxidant proteins and autophagy-related proteins. FOXO downregulation: ADAMTS-4↑ and Chemerin↑ in OA chondrocytes.
Huang et al. [47]	Knockdown of serum- and glucocorticoid-regulated kinase 1 (SGK1)	OA human chondrocyte	Activation	Prevention	SGK1 was upregulated in OA cartilage. SGK1 knockdown leads to increased autophagy, subsequently inhibiting OA by regulating FOXO1. SGK1 knockdown: collagen II↑, aggrecan↑, ADAMTS-5↓, MMP-13↓, disintegrin↓
Hwang et al. [48]	29 kDa fibronectin fragment (29 kDa FN-f)	OA human chondrocyte	Inhibition	Induction	HMGB1 level was significantly lower in human OA cartilage. 29-kDa FN-f inhibits chondrocyte autophagy by modulating the mTOR pathway and HMGB1 signaling pathway.
He et al. [49]	Hox transcript antisense intergenic RNA (HOTAIR)	OA human chondrocyte	Inhibition	Induction	Upregulation of HOTAIR and downregulation of miR130a-3p were found in OA. Expression of HOTAIR resulted in apoptosis events caused by the sponging of miR-130a-3p to suppress autophagy, subsequently induced OA.
Wang et al. [50]	Upregulated microRNA-590-5p (miR-590-5p)	Normal human chondrocyte	Activation	Induction	Mechanical pressure injury resulted in a significantly increased expression of miR-590-5p and decreased expression of TGFβ1. The miR-590-5p targets TGFβ1 to regulate chondrocyte apoptosis and autophagy in response to mechanical pressure injury. Decreased miR-590-5p leads to increased cell viability and decreased autophagy. And, decreased TGFβ1 leads to increased autophagy and apoptosis.

OA, osteoarthritis; mTOR, mammalian target of rapamycin; MMP, matrix metalloproteinase; IL, interleukin; ER, endoplasmic reticulum; NF-κB, nuclear factor-κB; ACAN, aggrecan; COL2, type II collagen; SOX9, SRY (sex determining region Y) box 9; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; Nrf2, nuclear factor (erythroid-derived 2)-like 2; AMPK, 5′-adenosine monophosphate-activated protein kinase; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; COX, cyclooxynenase; PGE, prostaglandin E; PPARG, peroxisome proliferator-activated receptor-γ; FOXO, forkhead-box class O; TSC, tuberous sclerosis complex; ULK1, unc-51 like autophagy activating kinase 1; HIF-1, hypoxia-inducible factor-1; TGF-β, transforming growth factor-β; TIMPs, tissue inhibitors of metalloproteinases; Atg, autophagy-related gene miRNA, mi-croRNA; FUT1, fucosyltransferase 1; MAP1LC3, microtubule-associated protein 1 light chain 3; GABARAPL1, gamma-aminobutyric acid receptor-associated protein-like 1; SYNV1, synoviolin1; HMGB1, high-mobility group protein box 1.