Abstract
Aging is a progressive and complicated bioprocess with overall decline in physiological function. Osteoarthritis (OA) is the most common joint disease in middle-aged and older populations. Since the prevalence of OA increases with age and breakdown of articular cartilage is its major hallmark, OA has long been thought of as “wear and tear” of joint cartilage. Nevertheless, recent studies have revealed that changes in the chondrocyte function and matrix components may reduce the material properties of articular cartilage and predispose the joint to OA. The aberrant gene expression in aging articular cartilage that is regulated by various epigenetic mechanisms plays an important role in age-related OA pathogenesis. This review begins with an introduction to the current understanding of epigenetic mechanisms, followed by mechanistic studies on the aging of joint tissues, epigenetic regulation of age-dependent gene expression in articular cartilage, and the significance of epigenetic mechanisms in OA pathogenesis. Our recent findings on age-dependent expression of 2 transcription factors, nuclear factor of activated T cell 1 (NFAT1) and SOX9, and their roles in the formation and aging of articular cartilage are summarized in the review. Chondrocyte dysfunction in aged mice, which is mediated by epigenetically regulated spontaneous reduction of NFAT1 expression in articular cartilage, is highlighted as an important advance in epigenetics and cartilage aging. Potential therapeutic strategies for age-related cartilage degeneration and OA using epigenetic molecular tools are discussed at the end.
References
1.
Zhang
M
, Egan
B
, Wang
J
. Epigenetic mechanisms underlying the aberrant catabolic and anabolic activities of osteoarthritic chondrocytes
. Int J Biochem Cell Biol
. 2015
Oct
;67
:101
–9
.
[PubMed]
1357-27252.
Li
Y
. Epigenetic Mechanisms Link Maternal Diets and Gut Microbiome to Obesity in the Offspring
. Front Genet
. 2018
Aug
;9
:342
.
[PubMed]
1664-80213.
Kim
S
, Wyckoff
J
, Morris
AT
, Succop
A
, Avery
A
, Duncan
GE
, et al. DNA methylation associated with healthy aging of elderly twins
. Geroscience
. 2018
Dec
;40
(5-6
):469
–84
.
[PubMed]
2509-27154.
Jin
B
, Robertson
KD
. DNA methyltransferases, DNA damage repair, and cancer
. Adv Exp Med Biol
. 2013
;754
:3
–29
.
[PubMed]
0065-25985.
Bird
A
. DNA methylation patterns and epigenetic memory
. Genes Dev
. 2002
Jan
;16
(1
):6
–21
.
[PubMed]
0890-93696.
Weber
M
, Hellmann
I
, Stadler
MB
, Ramos
L
, Pääbo
S
, Rebhan
M
, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome
. Nat Genet
. 2007
Apr
;39
(4
):457
–66
.
[PubMed]
1061-40367.
8.
Shi
Y
, Lan
F
, Matson
C
, Mulligan
P
, Whetstine
JR
, Cole
PA
, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1
. Cell
. 2004
Dec
;119
(7
):941
–53
.
[PubMed]
0092-86749.
Whetstine
JR
, Nottke
A
, Lan
F
, Huarte
M
, Smolikov
S
, Chen
Z
, et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases
. Cell
. 2006
May
;125
(3
):467
–81
.
[PubMed]
0092-867410.
Zhang
M
, Lygrisse
K
, Wang
J
. Role of MicroRNA in Osteoarthritis
. J Arthritis
. 2017
Apr
;6
(2
):6
.
[PubMed]
2167-792111.
Cefalu
CA
. Theories and mechanisms of aging
. Clin Geriatr Med
. 2011
Nov
;27
(4
):491
–506
.
[PubMed]
0749-069012.
Brunet
A
, Berger
SL
. Epigenetics of aging and aging-related disease
. J Gerontol A Biol Sci Med Sci
. 2014
Jun
;69
Suppl 1
:S17
–20
.
[PubMed]
1079-500613.
Greene
MA
, Loeser
RF
. Aging-related inflammation in osteoarthritis
. Osteoarthritis Cartilage
. 2015
Nov
;23
(11
):1966
–71
.
[PubMed]
1063-458414.
Wang
Y
, Karlsson
R
, Lampa
E
, Zhang
Q
, Hedman
AK
, Almgren
M
, et al. Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins
. Epigenetics
. 2018
;13
(9
):975
–87
.
[PubMed]
1559-229415.
Fraga
MF
, Ballestar
E
, Paz
MF
, Ropero
S
, Setien
F
, Ballestar
ML
, et al. Epigenetic differences arise during the lifetime of monozygotic twins
. Proc Natl Acad Sci USA
. 2005
Jul
;102
(30
):10604
–9
.
[PubMed]
0027-842416.
Matt
SM
, Allen
JM
, Lawson
MA
, Mailing
LJ
, Woods
JA
, Johnson
RW
. Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice
. Front Immunol
. 2018
Aug
;9
:1832
.
[PubMed]
1664-322417.
Chung
HY
, Sung
B
, Jung
KJ
, Zou
Y
, Yu
BP
: The molecular inflammatory process in aging.
Antioxidants & redox signaling 2006
;8:572-581. 18.
Nardini
C
, Moreau
JF
, Gensous
N
, Ravaioli
F
, Garagnani
P
, Bacalini
MG
. The epigenetics of inflammaging: the contribution of age-related heterochromatin loss and locus-specific remodelling and the modulation by environmental stimuli
. Semin Immunol
. 2018
Dec
;40
:49
–60
.
[PubMed]
1044-532319.
Franceschi
C
, Campisi
J
. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases
. J Gerontol A Biol Sci Med Sci
. 2014
Jun
;69
Suppl 1
:S4
–9
.
[PubMed]
1079-500620.
Huang
H
, Skelly
JD
, Ayers
DC
, Song
J
. Age-dependent Changes in the Articular Cartilage and Subchondral Bone of C57BL/6 Mice after Surgical Destabilization of Medial Meniscus
. Sci Rep
. 2017
Feb
;7
(1
):42294
.
[PubMed]
2045-232221.
Martin
JA
, Klingelhutz
AJ
, Moussavi-Harami
F
, Buckwalter
JA
. Effects of oxidative damage and telomerase activity on human articular cartilage chondrocyte senescence
. J Gerontol A Biol Sci Med Sci
. 2004
Apr
;59
(4
):324
–37
.
[PubMed]
1079-500622.
Philipot
D
, Guérit
D
, Platano
D
, Chuchana
P
, Olivotto
E
, Espinoza
F
, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis
. Arthritis Res Ther
. 2014
Feb
;16
(1
):R58
.
[PubMed]
1478-635423.
Verzijl
N
, DeGroot
J
, Ben
ZC
, Brau-Benjamin
O
, Maroudas
A
, Bank
RA
, et al. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis
. Arthritis Rheum
. 2002
Jan
;46
(1
):114
–23
.
[PubMed]
0004-359124.
Kapoor
M
, Martel-Pelletier
J
, Lajeunesse
D
, Pelletier
JP
, Fahmi
H
. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis
. Nat Rev Rheumatol
. 2011
Jan
;7
(1
):33
–42
.
[PubMed]
1759-479025.
Guerne
PA
, Zuraw
BL
, Vaughan
JH
, Carson
DA
, Lotz
M
. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis
. J Clin Invest
. 1989
Feb
;83
(2
):585
–92
.
[PubMed]
0021-973826.
Englund
M
, Guermazi
A
, Roemer
FW
, Aliabadi
P
, Yang
M
, Lewis
CE
, et al. Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study
. Arthritis Rheum
. 2009
Mar
;60
(3
):831
–9
.
[PubMed]
0004-359127.
Pauli
C
, Grogan
SP
, Patil
S
, Otsuki
S
, Hasegawa
A
, Koziol
J
, et al. Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis
. Osteoarthritis Cartilage
. 2011
Sep
;19
(9
):1132
–41
.
[PubMed]
1063-458428.
Hasegawa
A
, Otsuki
S
, Pauli
C
, Miyaki
S
, Patil
S
, Steklov
N
, et al. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis
. Arthritis Rheum
. 2012
Mar
;64
(3
):696
–704
.
[PubMed]
0004-359129.
Felson
DT
. Osteoarthritis as a disease of mechanics
. Osteoarthritis Cartilage
. 2013
Jan
;21
(1
):10
–5
.
[PubMed]
1063-458430.
Singh
T
, Newman
AB
. Inflammatory markers in population studies of aging
. Ageing Res Rev
. 2011
Jul
;10
(3
):319
–29
.
[PubMed]
1568-163731.
Loeser
RF
, Olex
AL
, McNulty
MA
, Carlson
CS
, Callahan
MF
, Ferguson
CM
, et al. Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice
. Arthritis Rheum
. 2012
Mar
;64
(3
):705
–17
.
[PubMed]
0004-359132.
Arda
HE
, Li
L
, Tsai
J
, Torre
EA
, Rosli
Y
, Peiris
H
, et al. Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function
. Cell Metab
. 2016
May
;23
(5
):909
–20
.
[PubMed]
1550-413133.
Hellio Le Graverand-Gastineau
MP
. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed?
Osteoarthritis Cartilage
. 2009
Nov
;17
(11
):1393
–401
.
[PubMed]
1063-458434.
Merrihew
C
, Kumar
B
, Heretis
K
, Rueger
DC
, Kuettner
KE
, Chubinskaya
S
: Alterations in endogenous osteogenic protein-1 with degeneration of human articular cartilage.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society 2003
;21:899-907. 35.
Loeser
RF
, Im
HJ
, Richardson
B
, Lu
Q
, Chubinskaya
S
. Methylation of the OP-1 promoter: potential role in the age-related decline in OP-1 expression in cartilage
. Osteoarthritis Cartilage
. 2009
Apr
;17
(4
):513
–7
.
[PubMed]
1063-458436.
Tsuji
K
, Cox
K
, Gamer
L
, Graf
D
, Economides
A
, Rosen
V
: Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society 2010
;28:384-389.37.
Bi
W
, Deng
JM
, Zhang
Z
, Behringer
RR
, de Crombrugghe
B
. Sox9 is required for cartilage formation
. Nat Genet
. 1999
May
;22
(1
):85
–9
.
[PubMed]
1061-403638.
Henry
SP
, Liang
S
, Akdemir
KC
, de Crombrugghe
B
: The postnatal role of Sox9 in cartilage.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2012
;27:2511-2525. 39.
Zhang
M
, Lu
Q
, Miller
AH
, Barnthouse
NC
, Wang
J
. Dynamic epigenetic mechanisms regulate age-dependent SOX9 expression in mouse articular cartilage
. Int J Biochem Cell Biol
. 2016
Mar
;72
:125
–34
.
[PubMed]
1357-272540.
Xanthoudakis
S
, Viola
JP
, Shaw
KT
, Luo
C
, Wallace
JD
, Bozza
PT
, et al. An enhanced immune response in mice lacking the transcription factor NFAT1
. Science
. 1996
May
;272
(5263
):892
–5
.
[PubMed]
0036-807541.
Wang
J
, Gardner
BM
, Lu
Q
, Rodova
M
, Woodbury
BG
, Yost
JG
, et al. Transcription factor Nfat1 deficiency causes osteoarthritis through dysfunction of adult articular chondrocytes
. J Pathol
. 2009
Oct
;219
(2
):163
–72
.
[PubMed]
0022-341742.
Rodova
M
, Lu
Q
, Li
Y
, Woodbury
BG
, Crist
JD
, Gardner
BM
, Yost
JG
, Zhong
XB
, Anderson
HC
, Wang
J
: Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2011
;26:1974-1986. 43.
Zhang
M
, Lu
Q
, Egan
B
, Zhong
XB
, Brandt
K
, Wang
J
. Epigenetically mediated spontaneous reduction of NFAT1 expression causes imbalanced metabolic activities of articular chondrocytes in aged mice
. Osteoarthritis Cartilage
. 2016
Jul
;24
(7
):1274
–83
.
[PubMed]
1063-458444.
Greenblatt
MB
, Ritter
SY
, Wright
J
, Tsang
K
, Hu
D
, Glimcher
LH
, et al. NFATc1 and NFATc2 repress spontaneous osteoarthritis
. Proc Natl Acad Sci USA
. 2013
Dec
;110
(49
):19914
–9
.
[PubMed]
0027-842445.
Rudolf
R
, Busch
R
, Patra
AK
, Muhammad
K
, Avots
A
, Andrau
JC
, et al. Architecture and expression of the nfatc1 gene in lymphocytes
. Front Immunol
. 2014
Feb
;5
:21
.
[PubMed]
1664-322446.
Zhou
B
, Wu
B
, Tompkins
KL
, Boyer
KL
, Grindley
JC
, Baldwin
HS
. Characterization of Nfatc1 regulation identifies an enhancer required for gene expression that is specific to pro-valve endocardial cells in the developing heart
. Development
. 2005
Mar
;132
(5
):1137
–46
.
[PubMed]
1011-637047.
Caldwell
KL
, Wang
J
. Cell-based articular cartilage repair: the link between development and regeneration
. Osteoarthritis Cartilage
. 2015
Mar
;23
(3
):351
–62
.
[PubMed]
1063-458448.
Makwana
K
, Patel
SA
, Velingkaar
N
, Ebron
JS
, Shukla
GC
, Kondratov
RV
. Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13
. Aging (Albany NY)
. 2017
Jul
;9
(7
):1825
–43
.
[PubMed]
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