Annals of the Rheumatic Diseases,
Год журнала:
2024,
Номер
83(8), С. 1048 - 1059
Опубликована: Март 13, 2024
Osteoarthritis
is
a
complex
disease
with
huge
public
health
burden.
Genome-wide
association
studies
(GWAS)
have
identified
hundreds
of
osteoarthritis-associated
sequence
variants,
but
the
effector
genes
underpinning
these
signals
remain
largely
elusive.
Understanding
chromosome
organisation
in
three-dimensional
(3D)
space
essential
for
identifying
long-range
contacts
between
distant
genomic
features
(e.g.,
and
regulatory
elements),
tissue-specific
manner.
Here,
we
generate
first
whole
genome
conformation
analysis
(Hi-C)
map
primary
osteoarthritis
chondrocytes
identify
novel
candidate
disease.
Nature,
Год журнала:
2023,
Номер
613(7944), С. 508 - 518
Опубликована: Янв. 18, 2023
Abstract
Population
isolates
such
as
those
in
Finland
benefit
genetic
research
because
deleterious
alleles
are
often
concentrated
on
a
small
number
of
low-frequency
variants
(0.1%
≤
minor
allele
frequency
<
5%).
These
survived
the
founding
bottleneck
rather
than
being
distributed
over
large
ultrarare
variants.
Although
this
effect
is
well
established
Mendelian
genetics,
its
value
common
disease
genetics
less
explored
1,2
.
FinnGen
aims
to
study
genome
and
national
health
register
data
500,000
Finnish
individuals.
Given
relatively
high
median
age
participants
(63
years)
substantial
fraction
hospital-based
recruitment,
enriched
for
end
points.
Here
we
analyse
from
224,737
15
diseases
that
have
previously
been
investigated
genome-wide
association
studies
(GWASs).
We
also
include
meta-analyses
biobank
Estonia
United
Kingdom.
identified
30
new
associations,
primarily
variants,
population.
A
GWAS
1,932
2,733
significant
associations
(893
phenome-wide
(PWS),
P
2.6
×
10
–11
)
at
2,496
(771
PWS)
independent
loci
with
807
(247
Among
these,
fine-mapping
implicated
148
(73
coding
associated
83
(42
Moreover,
91
(47
had
an
<5%
non-Finnish
European
individuals,
which
62
(32
were
by
more
twofold
Finland.
findings
demonstrate
power
bottlenecked
populations
find
entry
points
into
biology
through
low-frequency,
impact
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Фев. 3, 2023
Abstract
Osteoarthritis
(OA)
is
a
chronic
degenerative
joint
disorder
that
leads
to
disability
and
affects
more
than
500
million
population
worldwide.
OA
was
believed
be
caused
by
the
wearing
tearing
of
articular
cartilage,
but
it
now
commonly
referred
as
whole-joint
initiated
with
biochemical
cellular
alterations
in
synovial
tissues,
which
histological
structural
changes
ends
up
whole
tissue
dysfunction.
Currently,
there
no
cure
for
OA,
partly
due
lack
comprehensive
understanding
pathological
mechanism
initiation
progression
disease.
Therefore,
better
signaling
pathways
key
molecules
involved
pathogenesis
crucial
therapeutic
target
design
drug
development.
In
this
review,
we
first
summarize
epidemiology
including
its
prevalence,
incidence
burdens,
risk
factors.
We
then
focus
on
roles
regulation
pathways,
such
Wnt/β-catenin,
NF-κB,
focal
adhesion,
HIFs,
TGFβ/ΒΜP
FGF
regulators
AMPK,
mTOR,
RUNX2
onset
development
OA.
addition,
factors
associated
MMPs,
ADAMTS/ADAMs,
PRG4,
are
discussed
detail.
Finally,
provide
updates
current
clinical
therapies
trials
biological
treatments
drugs
Research
advances
basic
knowledge
cartilage
biology
will
have
significant
impact
translational
value
developing
strategies.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Дек. 10, 2022
Sirt6
has
been
implicated
as
a
key
regulator
in
aging-related
diseases,
including
osteoarthritis.
However,
its
functional
role
and
molecular
mechanism
chondrocyte
senescence
osteoarthritis
pathophysiology
remain
largely
undefined.
Here
we
show
that
deficiency
exaggerates
progression,
whereas
intra-articular
injection
of
adenovirus-Sirt6
markedly
attenuates
surgical
destabilization
medial
meniscus-induced
Mechanistically,
can
directly
interact
with
STAT5
deacetylate
STAT5,
thus
inhibiting
the
IL-15/JAK3-induced
translocation
from
cytoplasm
to
nucleus,
which
inactivates
IL-15/JAK3/STAT5
signaling.
Mass
spectrometry
revealed
deacetylated
conserved
lysine
163
on
STAT5.
Mutation
arginine
abolished
regulatory
effect
Sirt6.
In
vivo,
specific
ablation
chondrocytes
exacerbated
Pharmacological
activation
substantially
alleviated
senescence.
Taken
together,
by
Targeting
represents
promising
new
approach
for
Journal of Translational Medicine,
Год журнала:
2023,
Номер
21(1)
Опубликована: Май 31, 2023
Abstract
Background
Osteoarthritis
(OA)
is
one
of
the
most
prevalent
musculoskeletal
diseases
and
leading
cause
pain
disability
in
aged
population.
However,
underlying
biological
mechanism
has
not
been
fully
understood.
This
study
aims
to
reveal
causal
effect
circulation
metabolites
on
OA
susceptibility.
Methods
A
two-sample
Mendelian
Randomization
(MR)
analysis
was
performed
estimate
causality
GDMs
OA.
genome-wide
association
(GWAS)
486
used
as
exposure,
whereas
8
different
phenotypes,
including
any-site
(All
OA),
knee
and/or
hip
(knee/hip
OA,
spine
finger
thumb
(hand
were
set
outcomes.
Inverse-variance
weighted
(IVW)
for
calculating
estimates.
weight
mode,
median,
MR-egger,
MR-PRESSO
sensitive
analysis.
Furthermore,
metabolic
pathway
via
web-based
Metaconflict
4.0.
All
statistical
analyses
R
software.
Results
In
this
MR
analysis,
a
total
235
causative
associations
between
phenotypes
observed.
After
false
discovery
rate
(FDR)
correction
9
robust
7
(e.g.,
arginine,
kynurenine,
isovalerylcarnitine)
5
finally
identified.
Additionally,
eleven
significant
pathways
4
identified
by
Conclusion
The
finding
our
suggested
that
can
be
considered
useful
circulating
biomarkers
screening
prevention
clinical
practice,
also
serve
candidate
molecules
future
exploration
drug
target
selection.
Annals of the Rheumatic Diseases,
Год журнала:
2024,
Номер
83(7), С. 926 - 944
Опубликована: Фев. 7, 2024
Objectives
Single-cell
and
spatial
transcriptomics
analysis
of
human
knee
articular
cartilage
tissue
to
present
a
comprehensive
transcriptome
landscape
osteoarthritis
(OA)-critical
cell
populations.
Methods
RNA
sequencing
spatially
resolved
transcriptomic
technology
have
been
applied
characterise
the
cellular
heterogeneity
which
were
collected
from
8
OA
donors,
3
non-OA
control
total
19
samples.
The
novel
chondrocyte
population
marker
genes
interest
validated
by
immunohistochemistry
staining,
quantitative
real-time
PCR,
etc.
OA-critical
populations
through
integrative
analyses
publicly
available
bulk
data
large-scale
genome-wide
association
studies.
Results
We
identified
33
population-specific
that
define
11
populations,
including
9
known
2
new
is,
pre-inflammatory
(preInfC)
inflammatory
(InfC).
findings
make
this
an
important
addition
literature
include:
(1)
InfC
activates
mediator
MIF-CD74;
(2)
prehypertrophic
(preHTC)
hypertrophic
(HTC)
are
potentially
populations;
(3)
most
OA-associated
differentially
expressed
reside
in
surface
superficial
zone;
(4)
prefibrocartilage
(preFC)
is
major
contributor
stratification
patients
with
OA,
resulting
both
inflammatory-related
subtype
non-inflammatory-related
subtype.
Conclusions
Our
results
highlight
InfC,
preHTC,
preFC
HTC
as
potential
target
for
therapy.
Also,
we
conclude
profiling
those
might
be
used
stratify
patient
defining
cohorts
clinical
trials
precision
medicine.
Nature,
Год журнала:
2024,
Номер
635(8039), С. 657 - 667
Опубликована: Ноя. 20, 2024
Human
embryonic
bone
and
joint
formation
is
determined
by
coordinated
differentiation
of
progenitors
in
the
nascent
skeleton.
The
cell
states,
epigenetic
processes
key
regulatory
factors
that
underlie
lineage
commitment
these
cells
remain
elusive.
Here
we
applied
paired
transcriptional
profiling
approximately
336,000
nucleus
droplets
spatial
transcriptomics
to
establish
a
multi-omic
atlas
human
cranium
development
between
5
11
weeks
after
conception.
Using
combined
modelling
data,
characterized
regionally
distinct
limb
cranial
osteoprogenitor
trajectories
across
skeleton
further
described
networks
govern
intramembranous
endochondral
ossification.
Spatial
localization
clusters
our
situ
sequencing
data
using
new
tool,
ISS-Patcher,
revealed
mechanisms
progenitor
zonation
during
formation.
Through
trajectory
analysis,
predicted
potential
non-canonical
cellular
origins
for
chondrocytes
from
Schwann
cells.
We
also
introduce
SNP2Cell,
tool
link
cell-type-specific
polygenic
traits
such
as
osteoarthritis.
osteolineage
here,
simulated
silico
perturbations
genes
cause
monogenic
craniosynostosis
implicate
states
disease
mechanisms.
This
work
forms
detailed
dynamic
cartilage
maturation
advances
fundamental
understanding
cell-fate
determination
skeletal
development.