The Potential of Natural Compounds Regulating Autophagy in the Treatment of Osteoporosis

Figures & data

Figure 1 The main stage of autophagy process. The schematic diagram of the main stages of autophagy: initiation and nucleation, extension, closure and maturation, fusion.

Figure 2 In the pathological environment, abnormal autophagy of OCs and OBs, increased bone resorption and insufficient bone formation lead to osteoporosis.

Table 1 Regulatory Molecules of Autophagy in Osteoblast and Osteoclast

Regulators	Target Cell	Pathway	Main Finds	Reference
OSMR	BMSCs	ERK/autophagy signaling pathway	Silencing OMSR gene can alleviate ERK signal inactivation and enhance autophagy to promote osteoblast differentiation.	[116]
TUG1	BMSCs	AMPK/mTOR signaling pathway	Silencing TUG1 gene inhibits autophagy and osteoblast differentiation via AMPK/mTOR signaling pathway.	[119]
NIPA2	hFOB1.19	PINK1/Parkin signaling pathway	Silencing NIPA2 gene enhanced PINK1/Parkin-mediated mitophagy and down-regulated the function of osteoblasts.	[73]
c-Fos	BMMs	Beclin1, PI3K/Akt, TAK1/S6 signaling pathway	Overexpression of the c-Fos gene reverses OPG-mediated inhibition of osteoclastogenesis by activating Beclin1-induced autophagy	[121]
KIF2	RAW264.7	Beclin-1 signaling pathway	KIF2 knockdown significantly increases Beclin-1 expression, thereby regulating autophagy and osteoclast differentiation	[123]
JNK1	RAW264.7	Beclin-1/Bcl2 signaling pathway	Silencing of the JNK1 gene reduces autophagy and osteoclastogenesis, and Beclin-1 silencing blocks JNK1-promoted autophagy responses in OCPs	[125]
TET2	RAW264.7	Beclin-1/Bcl2 signaling pathway	Knockdown of Tet2 gene increases Bcl2 expression and decreases Beclin-1-dependent autophagy to reduce osteoclast differentiation	[126]
P2X7R	BMMs	Ca^2+/Calcineurin/NFATc1 signaling pathway	Knockdown of P2X7R gene inhibits Ca^2+/Calcineurin/NFATc1 inhibits autophagy and osteoclast bone resorption	[128]
TRPV4↓	RAW264.7	Ca^2+/Calcineurin/NFATc1 signaling pathway	Knockdown of TRPV4 gene inhibits autophagy via Ca^2+/calcineurin/NFATc1 pathway, thereby inhibiting osteoclast differentiation and osteoporosis.	[129]

Figure 3 Mechanism diagram of natural compounds regulating autophagy signaling pathway in osteoblasts. Different natural compounds regulate osteoblast autophagy through a variety of different molecular mechanisms, thereby affecting osteoblast differentiation or cell death.

Table 2 Structure, Dose, Cell Lines and Mechanism of Natural Products Regulating Autophagy of Osteoblasts in vitro

Compounds	Structure	Dose	Target Cell	Mechanism	Reference
Paeoniflorin		10, 20µML	MC3T3-E1	Paeoniflorin can attenuate osteoblast apoptosis by inhibiting Akt/mTOR pathway to enhance autophagy	[130]
Leonurine		2, 5, 10µM	BMSCs	Leonurine can promote osteoblast differentiation by inhibiting PI3K/Akt/mTOR pathway and activating autophagy.	[132]
Resveratrol		10^−8, 10^−7, 10^−6 M	MC3T3-E1	Resveratrol can enhance autophagy and SIRT1 expression through the PI3K/Akt/mTOR signaling pathway.	[135]
Geniposide		10, 20µM	MC3T3-E1	Geniposide can ameliorate osteoblast apoptosis by activating PI3K/AKT/mTOR to enhance autophagy.	[137]
β-ecdysterone		20, 40, 60μM	Rat primary osteoblasts	β-ecdysterone can inhibit PI3K/Akt/mTOR pathway to activate autophagy and reduce osteoblast apoptosis	[139]
Alpinetin		10, 20, 40 μM	BMSCs	Alpinetin can augment PKA/mTOR/ULK1 signaling pathway to enhance autophagy and promote osteoblast differentiation.	[140]
Timosaponin BII		0.1, 1, 10µM	Rat primary osteoblasts	Timosaponin BII can inhibit mTOR/NF-κB signaling pathway and activate autophagy to attenuate oxidative stress and apoptosis.	[142]
Cladrin		1, 10, 100 nM	Mice calvarial osteoblasts	Cladrin can induce autophagy through AMPK/mTOR signaling pathway to protect osteoblasts.	[144]
Aucubin		50, 100, 150 μM	MC3T3-E1	Aucubin can enhance autophagy by activating AMPK signaling pathway to avoid steroid-induced osteoblast apoptosis.	[145]
Trehalose		50, 100, 150, 200μM	hFOB 1.19	Trehalose can activate AMPK/mTOR/ULK1 pathway to induce autophagy and improve palmitic acid-induced apoptosis	[149]
Tetramethylpyrazine		50, 100, 200 μM	BMSCs	Tetramethylpyrazine can activate AMPK/mTOR to promote autophagy and protect BMSCs from apoptosis.	[150]
Cistanoside A		5, 10, 20 μM	Rat cranial osteoblasts	Cistanoside A can enhance osteoblast differentiation by inducing autophagy through the Wnt/β-catenin pathway.	[153]
Kaempferol		5, 10, 25, 50, 75, 100 µM	RAW264.7	Kaempferol can inhibit autophagy and activate osteoclast apoptosis through p62/SQSTM1 pathway.	[154]
Curcumin		5, 10, 15µM	BMMs	Curcumin can inhibit autophagy by inhibiting Beclin1 signaling, thereby causing an anti-osteoclast generation effect.	[156]
Orcinol glucoside		1, 5, 10µM	RAW264.7	Orcinol Glucoside can attenuate oxidative stress and osteoclast autophagy by activating Nrf2/Keap1 and mTOR signaling pathways.	[158]
Lycorine		1.6, 3.2µM	BMMs	Lycorine can inhibit autophagy through the mROS/TRPML1/TFEB axis, reducing the number and activity of osteoclasts.	[160]
Epigallocatechin-3-gallate		10,25,50 µM	RAW264.7	Epigallocatechin-3-gallate regulates mitophagy through AKT and p38MAPK pathways, thereby inhibiting OC differentiation.	[162]

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