Introduction: Osteoarthritis (OA) is a prevalent clinical chronic degenerative condition characterized by the degeneration of articular cartilage. Currently, drug treatments for OA come with varying degrees of side effects, making the development of new therapeutic approaches for OA imperative. Mesenchymal stem cells (MSCs) are known to mitigate the progression of OA primarily through paracrine effects. The conditioned medium (CM) derived from MSCs encapsulates a variety of paracrine factors secreted by these cells. Methods: In this study, we investigated the effect of the CM of infrapatellar fat pad-derived MSCs (IPFSCs) on OA in vitro and in vivo, as well as and the potential underlying mechanisms. We established three experimental groups: the normal group, the OA group, and the CM intervention group. In vitro experiments, we used methods such as qPCR, Western blot, immunofluorescence, and flow cytometry to detect the impact of CM on OA chondrocytes. In vivo experiments, we evaluated the changes in the knee joints of OA rats after intra-articular injection of CM treatment. Results: The results showed that injection of CM into the knee joint inhibited OA development in a rat model induced by destabilization of the medial meniscus and anterior cruciate ligament transection. The CM increased the deposition of extracellular matrix-related components (type II collagen and Proteoglycan). The activation of PI3K/AKT/NF-κB signaling pathway was induced by IL-1β in chondrocytes, which was finally inhibited by CM-IPFSCs treatment. Conclusion: In summary, IPFSCs-CM may have therapeutic potential for OA.

1.
Lotz
MK
,
Caramés
B
.
Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA
.
Nat Rev Rheumatol
.
2011
;
7
(
10
):
579
87
.
2.
Vos
T
,
Flaxman
AD
,
Naghavi
M
,
Lozano
R
,
Michaud
C
,
Ezzati
M
, et al
.
Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010
.
Lancet
.
2012
;
380
(
9859
):
2163
96
.
3.
Karsdal
MA
,
Michaelis
M
,
Ladel
C
,
Siebuhr
AS
,
Bihlet
AR
,
Andersen
JR
, et al
.
Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future
.
Osteoarthritis Cartilage
.
2016
;
24
(
12
):
2013
21
.
4.
Xia
B
,
Di
C
,
Zhang
J
,
Hu
S
,
Jin
H
,
Tong
P
.
Osteoarthritis pathogenesis: a review of molecular mechanisms
.
Calcif Tissue Int
.
2014
;
95
(
6
):
495
505
.
5.
Yan
S
,
Wang
M
,
Zhao
J
,
Zhang
H
,
Zhou
C
,
Jin
L
, et al
.
MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis
.
Int J Mol Med
.
2016
;
38
(
1
):
201
9
.
6.
Mi
B
,
Wang
J
,
Liu
Y
,
Liu
J
,
Hu
L
,
Panayi
AC
, et al
.
Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes
.
Front Pharmacol
.
2018
;
9
:
605
.
7.
McAlindon
TE
,
Bannuru
RR
,
Sullivan
MC
,
Arden
NK
,
Berenbaum
F
,
Bierma-Zeinstra
SM
, et al
.
OARSI guidelines for the non-surgical management of knee osteoarthritis
.
Osteoarthritis Cartilage
.
2014
;
22
(
3
):
363
88
.
8.
McGrory
B
,
Weber
K
,
Lynott
JA
,
Richmond
JC
,
Davis
CM
,
Yates
A
Jr
, et al
.
The American academy of orthopaedic surgeons evidence-based clinical practice guideline on surgical management of osteoarthritis of the knee
.
J Bone Joint Surg Am
.
2016
;
98
(
8
):
688
92
.
9.
Yao
X
,
Zhang
J
,
Jing
X
,
Ye
Y
,
Guo
J
,
Sun
K
, et al
.
Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission
.
Pharmacol Res
.
2019
;
139
:
314
24
.
10.
Jiang
YZ
,
Zhang
SF
,
Qi
YY
,
Wang
LL
,
Ouyang
HW
.
Cell transplantation for articular cartilage defects: principles of past, present, and future practice
.
Cell Transplant
.
2011
;
20
(
5
):
593
607
.
11.
de Windt
TS
,
Vonk
LA
,
Slaper-Cortenbach
IC
,
van den Broek
MP
,
Nizak
R
,
van Rijen
MH
, et al
.
Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons
.
Stem Cells
.
2017
;
35
(
1
):
256
64
.
12.
Hsu
YK
,
Sheu
SY
,
Wang
CY
,
Chuang
MH
,
Chung
PC
,
Luo
YS
, et al
.
The effect of adipose-derived mesenchymal stem cells and chondrocytes with platelet-rich fibrin releasates augmentation by intra-articular injection on acute osteochondral defects in a rabbit model
.
Knee
.
2018
;
25
(
6
):
1181
91
.
13.
Xia
T
,
Yu
F
,
Zhang
K
,
Wu
Z
,
Shi
D
,
Teng
H
, et al
.
The effectiveness of allogeneic mesenchymal stem cells therapy for knee osteoarthritis in pigs
.
Ann Transl Med
.
2018
;
6
(
20
):
404
.
14.
Colombini
A
,
Perucca Orfei
C
,
Kouroupis
D
,
Ragni
E
,
De Luca
P
,
ViganÒ
M
, et al
.
Mesenchymal stem cells in the treatment of articular cartilage degeneration: new biological insights for an old-timer cell
.
Cytotherapy
.
2019
;
21
(
12
):
1179
97
.
15.
Zhang
S
,
Jiang
YZ
,
Zhang
W
,
Chen
L
,
Tong
T
,
Liu
W
, et al
.
Neonatal desensitization supports long-term survival and functional integration of human embryonic stem cell-derived mesenchymal stem cells in rat joint cartilage without immunosuppression
.
Stem Cells Dev
.
2013
;
22
(
1
):
90
101
.
16.
Somoza
RA
,
Welter
JF
,
Correa
D
,
Caplan
AI
.
Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations
.
Tissue Eng Part B Rev
.
2014
;
20
(
6
):
596
608
.
17.
Yang
Z
,
Li
H
,
Yuan
Z
,
Fu
L
,
Jiang
S
,
Gao
C
, et al
.
Endogenous cell recruitment strategy for articular cartilage regeneration
.
Acta Biomater
.
2020
;
114
:
31
52
.
18.
Zhang
S
,
Hu
B
,
Liu
W
,
Wang
P
,
Lv
X
,
Chen
S
, et al
.
Articular cartilage regeneration: the role of endogenous mesenchymal stem/progenitor cell recruitment and migration
.
Semin Arthritis Rheum
.
2020
;
50
(
2
):
198
208
.
19.
Mamidi
MK
,
Das
AK
,
Zakaria
Z
,
Bhonde
R
.
Mesenchymal stromal cells for cartilage repair in osteoarthritis
.
Osteoarthritis Cartilage
.
2016
;
24
(
8
):
1307
16
.
20.
Meirelles
LS
,
Fontes
AM
,
Covas
DT
,
Caplan
AI
.
Mechanisms involved in the therapeutic properties of mesenchymal stem cells
.
Cytokine Growth Factor Rev
.
2009
;
20
(
5–6
):
419
27
.
21.
Bruno
S
,
Grange
C
,
Deregibus
MC
,
Calogero
RA
,
Saviozzi
S
,
Collino
F
, et al
.
Mesenchymal stem cell-derived microvesicles protect against acute tubular injury
.
J Am Soc Nephrol
.
2009
;
20
(
5
):
1053
67
.
22.
Zhu
D
,
Johnson
TK
,
Wang
Y
,
Thomas
M
,
Huynh
K
,
Yang
Q
, et al
.
Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb
.
Stem Cell Res Ther
.
2020
;
11
(
1
):
162
.
23.
Chen
W
,
Sun
Y
,
Gu
X
,
Hao
Y
,
Liu
X
,
Lin
J
, et al
.
Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy
.
J Tissue Eng Regen Med
.
2019
;
13
(
9
):
1618
28
.
24.
Soleimanifar
F
,
Hosseini
FS
,
Atabati
H
,
Behdari
A
,
Kabiri
L
,
Enderami
SE
, et al
.
Adipose-derived stem cells-conditioned medium improved osteogenic differentiation of induced pluripotent stem cells when grown on polycaprolactone nanofibers
.
J Cell Physiol
.
2019
;
234
(
7
):
10315
23
.
25.
Kouroupis
D
,
Kaplan
LD
,
Best
TM
.
Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures
.
Sci Rep
.
2022
;
12
(
1
):
3609
.
26.
Cosenza
S
,
Ruiz
M
,
Toupet
K
,
Jorgensen
C
,
Noël
D
.
Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis
.
Sci Rep
.
2017
;
7
(
1
):
16214
.
27.
Kay
AG
,
Long
G
,
Tyler
G
,
Stefan
A
,
Broadfoot
SJ
,
Piccinini
AM
, et al
.
Mesenchymal stem cell-conditioned medium reduces disease severity and immune responses in inflammatory arthritis
.
Sci Rep
.
2017
;
7
(
1
):
18019
.
28.
Wang
F
,
Liu
J
,
Chen
X
,
Zheng
X
,
Qu
N
,
Zhang
B
, et al
.
IL-1β receptor antagonist (IL-1Ra) combined with autophagy inducer (TAT-Beclin1) is an effective alternative for attenuating extracellular matrix degradation in rat and human osteoarthritis chondrocytes
.
Arthritis Res Ther
.
2019
;
21
(
1
):
171
.
29.
Li
J
,
Jiang
M
,
Xiong
C
,
Pan
J
,
Jia
S
,
Zhang
Y
, et al
.
KLF4, negatively regulated by miR-7, suppresses osteoarthritis development via activating TGF-β1 signaling
.
Int Immunopharmacol
.
2022
;
102
:
108416
.
30.
Wang
CJ
,
Cheng
JH
,
Chou
WY
,
Hsu
SL
,
Chen
JH
,
Huang
CY
.
Changes of articular cartilage and subchondral bone after extracorporeal shockwave therapy in osteoarthritis of the knee
.
Int J Med Sci
.
2017
;
14
(
3
):
213
23
.
31.
Gerwin
N
,
Bendele
AM
,
Glasson
S
,
Carlson
CS
.
The OARSI histopathology initiative: recommendations for histological assessments of osteoarthritis in the rat
.
Osteoarthritis Cartilage
.
2010
;
18
(
Suppl 3
):
S24
34
.
32.
Yamadera
M
,
Shinto
E
,
Kajiwara
Y
,
Mochizuki
S
,
Okamoto
K
,
Shimazaki
H
, et al
.
Differential clinical impacts of tumour budding evaluated by the use of immunohistochemical and haematoxylin and eosin staining in stage II colorectal cancer
.
Histopathology
.
2019
;
74
(
7
):
1005
13
.
33.
Lin
H
,
Chen
H
,
Qi
B
,
Jiang
Y
,
Lian
N
,
Zhuang
X
, et al
.
Brain-derived extracellular vesicles mediated coagulopathy, inflammation and apoptosis after sepsis
.
Thromb Res
.
2021
;
207
:
85
95
.
34.
Liu
Z
,
Liu
R
,
Wang
R
,
Dai
J
,
Chen
H
,
Wang
J
, et al
.
Sinensetin attenuates IL-1β-induced cartilage damage and ameliorates osteoarthritis by regulating SERPINA3
.
Food Funct
.
2022
;
13
(
19
):
9973
87
.
35.
Huseynov
E
.
Novel nanomaterials for hepatobiliary diseases treatment and future perspectives
.
Adv Biol Earth Sci
.
2024
;
9
(
Special Issue
):
81
91
.
36.
Khalilov
RK
.
Future prospects of biomaterials in nanomedicine
.
Adv Biol Earth Sci
.
2024
;
9
(
Special Issue
):
5
10
.
37.
Rosic
G
.
Cancer signaling, cell/gene therapy, diagnosis and role of nanobiomaterials
.
Adv Biol Earth Sci
.
2024
;
9
(
Special Issue
):
11
34
.
38.
Toh
WS
,
Lai
RC
,
Hui
JHP
,
Lim
SK
.
MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment
.
Semin Cell Dev Biol
.
2017
;
67
:
56
64
.
39.
Charlier
E
,
Relic
B
,
Deroyer
C
,
Malaise
O
,
Neuville
S
,
Collée
J
, et al
.
Insights on molecular mechanisms of chondrocytes death in osteoarthritis
.
Int J Mol Sci
.
2016
;
17
(
12
):
2146
.
40.
Musumeci
G
,
Aiello
FC
,
Szychlinska
MA
,
Di Rosa
M
,
Castrogiovanni
P
,
Mobasheri
A
.
Osteoarthritis in the XXIst century: risk factors and behaviours that influence disease onset and progression
.
Int J Mol Sci
.
2015
;
16
(
3
):
6093
112
.
41.
Rahmati
M
,
Nalesso
G
,
Mobasheri
A
,
Mozafari
M
.
Aging and osteoarthritis: central role of the extracellular matrix
.
Ageing Res Rev
.
2017
;
40
:
20
30
.
42.
Yang
J
,
Hu
S
,
Bian
Y
,
Yao
J
,
Wang
D
,
Liu
X
, et al
.
Targeting cell death: pyroptosis, ferroptosis, apoptosis and necroptosis in osteoarthritis
.
Front Cell Dev Biol
.
2021
;
9
:
789948
.
43.
Sellam
J
,
Berenbaum
F
.
The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis
.
Nat Rev Rheumatol
.
2010
;
6
(
11
):
625
35
.
44.
Greif
DN
,
Kouroupis
D
,
Murdock
CJ
,
Griswold
AJ
,
Kaplan
LD
,
Best
TM
, et al
.
Infrapatellar fat pad/synovium complex in early-stage knee osteoarthritis: potential new target and source of therapeutic mesenchymal stem/stromal cells
.
Front Bioeng Biotechnol
.
2020
;
8
:
860
.
45.
Amodeo
G
,
Niada
S
,
Moschetti
G
,
Franchi
S
,
Savadori
P
,
Brini
AT
, et al
.
Secretome of human adipose-derived mesenchymal stem cell relieves pain and neuroinflammation independently of the route of administration in experimental osteoarthritis
.
Brain Behav Immun
.
2021
;
94
:
29
40
.
46.
Giannasi
C
,
Niada
S
,
Magagnotti
C
,
Ragni
E
,
Andolfo
A
,
Brini
AT
.
Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles
.
Stem Cell Res Ther
.
2020
;
11
(
1
):
521
.
47.
Roman-Blas
JA
,
Jimenez
SA
.
NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis
.
Osteoarthritis Cartilage
.
2006
;
14
(
9
):
839
48
.
48.
Li
YN
,
Fan
ML
,
Liu
HQ
,
Ma
B
,
Dai
WL
,
Yu
BY
, et al
.
Dihydroartemisinin derivative DC32 inhibits inflammatory response in osteoarthritic synovium through regulating Nrf2/NF-κB pathway
.
Int Immunopharmacol
.
2019
;
74
:
105701
.
49.
Schuliga
M
.
NF-kappaB signaling in chronic inflammatory airway disease
.
Biomolecules
.
2015
;
5
(
3
):
1266
83
.
50.
Liu
B
,
Ding
F
,
Hu
D
,
Zhou
Y
,
Long
C
,
Shen
L
, et al
.
Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro
.
Stem Cell Res Ther
.
2018
;
9
(
1
):
7
.
51.
Su
VY
,
Lin
CS
,
Hung
SC
,
Yang
KY
.
Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κB pathway in endotoxin-induced acute lung injury
.
Int J Mol Sci
.
2019
;
20
(
9
):
2208
.
52.
Song
HP
,
Chu
ZG
,
Zhang
DX
,
Dang
YM
,
Zhang
Q
.
PI3K-AKT pathway protects cardiomyocytes against hypoxia-induced apoptosis by MitoKATP-mediated mitochondrial translocation of pAKT
.
Cell Physiol Biochem
.
2018
;
49
(
2
):
717
27
.
53.
Li
W
,
Zhao
R
,
Wang
X
,
Liu
F
,
Zhao
J
,
Yao
Q
, et al
.
Nobiletin-ameliorated lipopolysaccharide-induced inflammation in acute lung injury by suppression of NF-κB pathway in vivo and vitro
.
Inflammation
.
2018
;
41
(
3
):
996
1007
.
54.
Oh
HA
,
Kwak
J
,
Kim
BJ
,
Jin
HJ
,
Park
WS
,
Choi
SJ
, et al
.
Migration inhibitory factor in conditioned medium from human umbilical cord blood-derived mesenchymal stromal cells stimulates hair growth
.
Cells
.
2020
;
9
(
6
):
1344
.
55.
Kim
YJ
,
Ahn
HJ
,
Lee
SH
,
Lee
MH
,
Kang
KS
.
Effects of conditioned media from human umbilical cord blood-derived mesenchymal stem cells in the skin immune response
.
Biomed Pharmacother
.
2020
;
131
:
110789
.
56.
Dahbour
S
,
Jamali
F
,
Alhattab
D
,
Al-Radaideh
A
,
Ababneh
O
,
Al-Ryalat
N
, et al
.
Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: clinical, ophthalmological and radiological assessments of safety and efficacy
.
CNS Neurosci Ther
.
2017
;
23
(
11
):
866
74
.
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