Role of Leptin in the
Pathophysiology of Osteoarthritis
Mohamed Aoulad Aissa, Aline Delalandre
Daniel Lajeunesse Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame,
Introduction
•Osteoarthritis (OA ) is characterized by: - Progressive articular cartilage loss - Bone sclerosis of the subchondral trabeculae and growth plate - formation of osteophytes
• OA risk factors: - Age (1/3 over 65 ) - Sex ( > women over 50) - Heredity - Obesity
• Adipocytes share a common mesenchymal stem cell precursor with osteoblasts, chondrocytes, tenocytes, and myoblasts, all affected by OA.
OA bone: Bone sclerosis: increased osteoid tissueIncreased trabecular thickness (Tb.Th)Decreased trabecular space (Tb. Sp.)
Hence: Altered mecanical properties Increased tissue rigidity
Decreased shock absorbing capacities
Caracteristics of osteoarthritic subchondral bone
Normal OA
Role of Leptin in Joint Tissues Metabolism
• Leptin has dual effects, both central and local, depending on bone tissue, skeletal maturity and/or signaling.
• Leptin plays a role in endochondral ossification possibly via its influence on angiogenesis due to enhanced MMP-2 activity.
• Leptin acts as a growth factor for chondrocytes in young individuals yet its role on mature chondrocytes is unclear.
• Leptin enhances the metabolic markers of osteoblasts i.e. ALPase, osteocalcin, Coll1, IGF-1 and TGF-, all of which are elevated in OA osteoblasts.
HYPOTHESIS
The local increase in leptin production and/or leptin
signaling in OA Ob leads to the abnormal osteoblast cell function
observed in OA and possibly abnormal bone remodeling in this
pathology. This also facilitates cartilage deterioration and loss.
Phenotypic characteristics of normal and OASubchcondral osteoblasts
Normal OA0
200
400
600
800
1000
1200
1400
Normal OA0
100
200
300
400
500
Alk
alin
e ph
osph
atas
e(n
mol
/mg
prot
ein/
30 m
in
Ost
eoca
lcin
(ng
/mg
prot
ein/
48 h p<0.01p<0.02
Leptin expression by OA osteoblasts, chondrocytes andSynoviocytes by Real-time PCR
Osteoblasts Chondrocytes Synoviocytes0.000e+0
1.000e-4
2.000e-4
3.000e-4
4.000e-4
Lep1
Lep2
Lepti
n/G
APD
H r
ati
o
Normal OA0.00
0.05
0.10
0.15
0.20
0.25Le
pti
n/G
APD
H (
rela
tive v
alu
e)
Leptin release by normal and OA Osteoblasts by Real-time PCR
Leptin release by normal and OA Osteoblasts
Normal OA0
20
40
60
80
100
Lep
tin
(p
g/m
g p
rote
in/4
8 h
) p<0.025
Regulation of Leptin Expression in OA OsteoblastsMeasured by Real-time PCR
Basal HGF TGF D3 D3 + HGF0
2
4
6
8
10
12Le
pti
n e
xpre
ssio
n (
rela
tive v
alu
e)
p<0.01
p<0.01
p<0.01
Basal + anti OB-RL0
100
200
300
400O
steoca
lcin
(ng/m
g p
rote
in/4
8 h
p<0.05
Effect of anti leptin receptor (OB-RL) antibodies onosteocalcin secretion by OA osteoblasts
Effect of anti leptin receptor (OB-RL) antibodies onalkaline phosphatase activity in OA osteoblasts
Basal + anti OB-RL
A
lkalin
e p
hosp
hata
se (
nm
ol/m
g p
rote
in/3
0 m
in)
0
200
400
600
800
1000
1200p<0.05
Basal D3 D3 + leptin D3 +anti leptin
0
200
400
600
800
1000
1200
1400
A
lkalin
e p
hosp
hata
se(n
mol/m
g p
rote
in/3
0 m
in)
Effect of leptin on alkaline phosphatase activityin OA osteoblasts
85
6050
Ctr
1,25
(OH
) 2D 3
Lep
Exo
TG
FH
GF
M
Induction of Leptin Receptor (OB-RB) in human osteoblasts treated with leptin, D3, TGF, or HGF. Leptin Receptors were detected with a monoclonal anti-OB-RB
antibody.
Regulation of Leptin Receptor Production in OA OsteoblastsMeasured by Western blot
DISCUSSION
Leptin expression was restricted to subchondral Ob whereaswe could not detect significant expression in chondrocytesnor synoviocytes. This would suggest that leptin found inarticular cartilage must be due to this production by Ob.
OA Ob produced more leptin than normal Ob. Enhancedleptin production by OA subchondral bone tissue maycontribute to both abnormal expression of cellular markersby Ob and inflammation, leading to loss of cartilage.
The interaction between TGF-, HGF, 1,25(OH)2D3 and leptin that exist in OA bone tissue needs to be studied further.
Osteoblasts Osteoclast
IL-6IGF-1TGF-PGE2
Tidemark
Micro-fractureuPA, IGF-1
IL-1 IL-6 IGF-1 TNF
TGF-bFGF
LeptinHGF
CollagenasesGelatinasesStromelysin
NO, free radicals
HGF/NK2
Trabecular bone
Subchondralbone
Cartilage
OsteoblastsOsteoclast
IL-6IGF-1TGF-PGE2
Tidemark
Micro-fractureuPA, IGF-1
IL-1 IL-6IGF-1 TNFTGF-bFGF
Leptin
CollagenasesGelatinasesStromelysin
NO, free radicals
Trabecular bone
Subchondralbone
Cartilage
?
?
Inflammation
IL-1/IFN
Acknowledgments
Daniel Lajeunesse
Aline Delalandre
Denis Couchourel