Introduction: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. Methods: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. Conclusion: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.

1.
Martel-Pelletier
J
,
Barr
AJ
,
Cicuttini
FM
,
Conaghan
PG
,
Cooper
C
,
Goldring
MB
,
Osteoarthritis
.
Nat Rev Dis Primers
.
2016
;
2
:
16072
.
2.
Abramoff
B
,
Caldera
FE
.
Osteoarthritis: pathology, diagnosis, and treatment options
.
Med Clin North Am
.
2020
;
104
(
2
):
293
311
. .
3.
Tsujii
A
,
Nakamura
N
,
Horibe
S
.
Age-related changes in the knee meniscus
.
Knee
.
2017
;
24
(
6
):
1262
70
. .
4.
Zhang
W
,
Randell
EW
,
Sun
G
,
Likhodii
S
,
Liu
M
,
Furey
A
,
Hyperglycemia-related advanced glycation end-products is associated with the altered phosphatidylcholine metabolism in osteoarthritis patients with diabetes
.
PLoS One
.
2017
;
12
(
9
):
e0184105
.
5.
Aiello
FC
,
Trovato
FM
,
Szychlinska
MA
,
Imbesi
R
,
Castrogiovanni
P
,
Loreto
C
,
Molecular links between diabetes and osteoarthritis: the role of physical activity
.
Curr Diabetes Rev
.
2017
;
13
(
1
):
50
8
.
6.
Saudek
DM
,
Kay
J
.
Advanced glycation endproducts and osteoarthritis
.
Curr Rheumatol Rep
.
2003
;
5
(
1
):
33
40
. .
7.
Li
Y
,
Zhang
Y
,
Chen
C
,
Zhang
H
,
Ma
C
,
Xia
Y
.
Establishment of a rabbit model to study the influence of advanced glycation end products accumulation on osteoarthritis and the protective effect of pioglitazone
.
Osteoarthritis Cartilage
.
2016
;
24
(
2
):
307
14
. .
8.
Xu
C
,
Sheng
S
,
Dou
H
,
Chen
J
,
Zhou
K
,
Lin
Y
,
α-Bisabolol suppresses the inflammatory response and ECM catabolism in advanced glycation end products-treated chondrocytes and attenuates murine osteoarthritis
.
Int Immunopharmacol
.
2020
;
84
:
106530
.
9.
Li
X
,
Jia
F
,
Zhu
Z
,
Huang
L
.
Lixisenatide attenuates advanced glycation end products (AGEs)-induced degradation of extracellular matrix in human primary chondrocytes
.
Artif Cells Nanomed Biotechnol
.
2019
;
47
(
1
):
1256
64
. .
10.
Blanco
FJ
,
Valdes
AM
,
Rego-Pérez
I
.
Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes
.
Nat Rev Rheumatol
.
2018
;
14
(
6
):
327
40
. .
11.
Rego-Perez
I
,
Fernandez-Moreno
M
,
Soto-Hermida
A
,
Fenandez-Lopez
C
,
Oreiro
N
,
Blanco
FJ
.
Mitochondrial genetics and osteoarthritis
.
Front Biosci
.
2013
;
5
:
360
8
. .
12.
Cillero-Pastor
B
,
Caramés
B
,
Lires-Deán
M
,
Vaamonde-García
C
,
Blanco
FJ
,
López-Armada
MJ
.
Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes
.
Arthritis Rheum
.
2008
;
58
(
8
):
2409
19
. .
13.
Vaamonde-García
C
,
Riveiro-Naveira
RR
,
Valcárcel-Ares
MN
,
Hermida-Carballo
L
,
Blanco
FJ
,
López-Armada
MJ
.
Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes
.
Arthritis Rheum
.
2012
;
64
(
9
):
2927
36
.
14.
Yang
Q
,
Guo
S
,
Wang
S
,
Qian
Y
,
Tai
H
,
Chen
Z
.
Advanced glycation end products-induced chondrocyte apoptosis through mitochondrial dysfunction in cultured rabbit chondrocyte
.
Fundam Clin Pharmacol
.
2015
;
29
(
1
):
54
61
. .
15.
Wang
J
,
Li
J
,
Song
D
,
Ni
J
,
Ding
M
,
Huang
J
,
AMPK: implications in osteoarthritis and therapeutic targets
.
Am J Transl Res
.
2020
;
12
(
12
):
7670
81
.
16.
Chen
LY
,
Wang
Y
,
Terkeltaub
R
,
Liu-Bryan
R
.
Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function
.
Osteoarthritis Cartilage
.
2018
;
26
(
11
):
1539
50
. .
17.
Terkeltaub
R
,
Yang
B
,
Lotz
M
,
Liu-Bryan
R
.
Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α
.
Arthritis Rheum
.
2011
;
63
(
7
):
1928
37
. .
18.
Zhou
S
,
Lu
W
,
Chen
L
,
Ge
Q
,
Chen
D
,
Xu
Z
,
AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice
.
Sci Rep
.
2017
;
7
:
43245
.
19.
Qiu
L
,
Luo
Y
,
Chen
X
.
Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats
.
Biomed Pharmacother
.
2018
;
103
:
1585
91
. .
20.
Zhao
X
,
Petursson
F
,
Viollet
B
,
Lotz
M
,
Terkeltaub
R
,
Liu-Bryan
R
.
Peroxisome proliferator-activated receptor γ coactivator 1α and FoxO3A mediate chondroprotection by AMP-activated protein kinase
.
Arthritis Rheumatol
.
2014
;
66
(
11
):
3073
82
. .
21.
Ma
H
,
Li
SY
,
Xu
P
,
Babcock
SA
,
Dolence
EK
,
Brownlee
M
,
Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy
.
J Cell Mol Med
.
2009
;
13
(
8B
):
1751
64
.
22.
Li
Q
,
Wu
S
,
Li
SY
,
Lopez
FL
,
Du
M
,
Kajstura
J
,
Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage
.
Am J Physiol Heart Circ Physiol
.
2007
;
292
(
3
):
H1398
403
.
23.
Wang
Y
,
Zhao
X
,
Lotz
M
,
Terkeltaub
R
,
Liu-Bryan
R
.
Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α
.
Arthritis Rheumatol
.
2015
;
67
(
8
):
2141
53
. .
24.
Carling
D
.
AMPK signalling in health and disease
.
Curr Opin Cell Biol
.
2017
;
45
:
31
7
. .
25.
Petursson
F
,
Husa
M
,
June
R
,
Lotz
M
,
Terkeltaub
R
,
Liu-Bryan
R
.
Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes
.
Arthritis Res Ther
.
2013
;
15
(
4
):
R77
. .
26.
Ruderman
NB
,
Xu
XJ
,
Nelson
L
,
Cacicedo
JM
,
Saha
AK
,
Lan
F
,
AMPK and SIRT1: a long-standing partnership?
Am J Physiol Endocrinol Metab
.
2010
;
298
(
4
):
E751
60
.
27.
Yang
Q
,
Chen
C
,
Wu
S
,
Zhang
Y
,
Mao
X
,
Wang
W
.
Advanced glycation end products downregulates peroxisome proliferator-activated receptor γ expression in cultured rabbit chondrocyte through MAPK pathway
.
Eur J Pharmacol
.
2010
;
649
(
1–3
):
108
14
. .
28.
Huang
H
,
Wang
ZJ
,
Zhang
HB
,
Liang
JX
,
Cao
WD
,
Wu
Q
,
The function of PPARγ/AMPK/SIRT-1 pathway in inflammatory response of human articular chondrocytes stimulated by advanced glycation end products
.
Biol Pharm Bull
.
2019
;
42
(
8
):
1303
9
.
29.
Bolduc
JA
,
Collins
JA
,
Loeser
RF
.
Reactive oxygen species, aging and articular cartilage homeostasis
.
Free Radic Biol Med
.
2019
;
132
:
73
82
. .
30.
Reed
KN
,
Wilson
G
,
Pearsall
A
,
Grishko
VI
.
The role of mitochondrial reactive oxygen species in cartilage matrix destruction
.
Mol Cell Biochem
.
2014
;
397
(
1–2
):
195
201
. .
31.
Hosseinzadeh
A
,
Kamrava
SK
,
Joghataei
MT
,
Darabi
R
,
Shakeri-Zadeh
A
,
Shahriari
M
,
Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin
.
J Pineal Res
.
2016
;
61
(
4
):
411
25
.
32.
St-Pierre
J
,
Drori
S
,
Uldry
M
,
Silvaggi
JM
,
Rhee
J
,
Jäger
S
,
Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators
.
Cell
.
2006
;
127
(
2
):
397
408
.
33.
Pardo
PS
,
Boriek
AM
.
An autoregulatory loop reverts the mechanosensitive Sirt1 induction by EGR1 in skeletal muscle cells
.
Aging
.
2012
;
4
(
7
):
456
61
. .
34.
Olmos
Y
,
Valle
I
,
Borniquel
S
,
Tierrez
A
,
Soria
E
,
Lamas
S
,
Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes
.
J Biol Chem
.
2009
;
284
(
21
):
14476
84
.
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