Osteoarthritis Flashcards
what is the role of cartilage in the ECM? How does it achieve these functions?
it forms a meshwork and gives the ECM mechanical strength and compression resistance
> can entrap large sulphated proteoglycans which can retain water
> articular cartilage allows for frictionless movement between joints
what is the most abundant ECM molecule?
what is its function?
collagen - makes up 25% of total protein mass in mammals
creates a meshwork and compression resistance
what is the 2nd most abundant
ECM molecule? what do they do?
it is proteoglycan (protein core + a sulphated GAG)
they can be sulphated or unsulphated (hyaluronic acid). and are highly charged molecules so can retain water creating a large swelling pressure making ECM compression resistant and gives stiffness to tissue!
> loss of PG linked to aging = increased pain of joints as no longer compression resistant
> hyaluronic acid can be found in synovial fluid enabling frictionless joint movement
how is cartilage homeostasis controlled?
via matrix metalloprotreases + ADAMT which degradE cartlidge and require a metal ion to be activated, maximum activity at a neutal pH
> THEY can remodel the ECM
but if excess =OA so are normally secreted in their inactive form (proenzyme/zymogen)
which joint is most likely to develop OA?
A hip
B shoulder
C knee
D waist
the knee
higher prevelance in women of getting OA than men due to a loss of cartilidge and then there is bone to bone contact
in OA what causes this uncontrolled degradation of cartiliage/what causes upregulation of MMP expression?
there is a disruption to chondrocyte metabolism so there is release of inflammatory mediators like ROS and cytokines
they upregulate NF-Kappa signalling which then upregulates MMP transcription and eventual secretion into the ECM
briefly decribe OA/ key characteristics
>molecular
> progressive loss of Articular Cartilage
new (ectopic) bone formation
synovial proliferation and inflammation
what is the key consequence of OA
painful joint as no longer frictionless movement
loss of joint function
is there a cure for OA?
no cure, there are no disease modifying agents available to stop or reverse OA progression
why is there no cure for OA?
it is a heterogenous disease, affecting the whole joint and multiple tissues therefore multiple combination therapies would be needed to effectively cure the disease
there are no diagnostic markers
what are the risk factors for developing OA?
age, obesity, genetic predisposition
OA has multifactorial epidemiology and coupled to Low QOL and comorbidities (mental decline)
what are the features of a synovial joint
avascular
alymphatic
aneural
which can make it difficult to deliver drugs
what is the role of chondrocytes?
they secrete and maintain the ECM (collagen and PG)
Derived from chrondroblasts
what type of collagen do chrondrocytes secretes in AC?
A type 1
B type 2
C type 9
D type 10
in articular cartlidge HEALTHY chondrocytes secrete type 2B collagen
whilst chondroblasts (progenitor cell) secrete type2A collagen
what type of collagen do chrondrocytes secretes in growth plate?
A type 1
B type 2
C type 9
D type 10
type 10 collagen
the growth plate is characterised by larger hypertrophic cartilidge and enable endochondral ossification to occure when the chondrocytes die
what are the properties of articular cartilage?
type 2 collegen provides tensile strength
aggrecan, a PG can retain water and provide compressive stiffness
what is the difference between healthy and pathological chondrocytes?
healthy chondrocytes are highly uniform and are terminally differentiated once mature
only type2B collagen expressed in AC
during pathology chondrocytes undergo phenotypic shift and express other collagens types including type 10 in the deep zone
and can revert back to IMMATURE state/ type2A collagen
what do chondrocytes secrete to survive in an avascular environment?
the joint is hypoxic environment so chondrocytes secrete HIF1-alpha
Hypoxia inducible factor
(simply) what causes OA? What occurs for degradation of joint to occur?
there is an imbalance between synthesis and degradation
anabolic activity outcompetes leading to tissue degradation and abnormal cartilidge matrix synthesis
what is arthritis?
umbrella term for diseases that cause joint pain and limit movement
OA - bone joint
RA - autoimmune attack on joints
what is the tidemark?
the tidemark separates the AC from the calcified cartilidge
how does the tidemark change in OA?
the tidemark advances as in late stage OA there is mineralisation
so calcified cartilige zone expands/subchondral bone thickens and vascular invasion of bone occurs
what are the steps of OA degradation?
biosynthetic phase - attempt to repair tissue (short-term). Chondrocytes undergo phenotypic shift but net loss of PG at surface
degradative phase - progressive thinning and loss of AC. Erosion accelerates
Mineralisation, vascularisation and osteophyte forms
what is a hallmark of OA
loss of surface PG, thinner smoother AC surface
what occurs during phenotypic shift?
Chrondrocyte attempts to repair damage by increasing anabolic activitity
but actually revert to an immature state or become hypertrophic
so net loss of Proteogylcans at superficial zone
what happens to bone during late stage OA?
becomes eburnated bone and polished.
subchondral plate thickens but less mineralisation so bone is soft weak and less resilient
lesions can occur and correlate with pain
osteophytes can form
how to diagnose OA?
Xray to identify joint space narrowing (as reduced AC)
MRI used to identify osteophytes, lesions, subchondral schlerosis
how to treat OA?
non-operative methods like NSAIDS, weightloss, physiotherapy to manage pain
HA supplements, corticosteroid injections to try and modulate damage
total joint replacement
is OA an inflammatory disease?
no as there leukocytes are below threshold and there is no systemic manifestation
so different from RA
> but obesity induced OA could be thought as it
how does colour of SF change in OA?
usually yellow straw coloured
if inflammed then more white blood cells so colour lighter and whiter
can syonovial fluid be used to diagnose OA?
SF contains a range of biomarkers for OA and have higher conc than in blood or urine
direct measure of the intraarticular environment
name some SF biomarkers
synovial cells and chondrocytes produce inflammatory cytokine
> IL-8, IL-6, TNF alpha
> c-telopeptide
> MMPs
what is the synovium/ synovial membrane?
is is a layer of connective tissue lining the joint capsule
2 layers - the intima and subintima
what are the functions of synovial fluid?
> controls fluid volume and composition
> provides nutrients and O2 to chondrocytes by diffusion
> acts a lubricant
what is synovitis?
when the synovium becomes inflamed as synoviocytes and chondrocytes secrete pro-i cytokines and matrix degrading protreases
SF effusion results in thickening of knee, pain heat and swelling
how does synovitis relate to OA?
present before cartilage degradation so could be indicative of early OA
synovitis progression -> furthur cartilage degradation
how does Synovial membrane differ from AC?
many more cell types like macrophages, dendritic cells, lymph, mast, granuloctes
fibroblasts and synoviocytes producing SF
it is vascularised tissue too!
how do pro-i cytokines (TNF-alpha, IL-beta) influence OA progression?
disturb balance
promote catabolism and block anabolism/prevent ECM synthesis
> encourage production of MMP and ADAMTS4/
how does IL-B act to furthur progress inflammatory process?
acts autocrine manner to increase its own production
stimulates synoviocytes and chondrocytes to produce cytokines
stimulate prostaglandin, another pro-i production#
this all results in chronic inflammation and tissue damage
how does IL-6 act
produced by sy+cho-cytes in response to IL-B signals
stimulates chondrocyte proliferation and osteocytes formation
how do adipokines influence OA?
obesity is a risk factor for OA as there is extra joint loading
adipose tissue can secrete cytokines
leptin receptor found on chondrocytes and can induce MMP and pro-i-cyto production
how does neovascularisation occur?
angiogenesis is paired with new nerve vessel formation which can contribute to pain
vascularisation of the AC can occur at the osteo/chonral and synovium function
how does the inflammatory response occur in OA?
ECM breakdown products lie decorin and hyaluran are exposed to SF instead of remaining in ECM
DAMPS and PRreceptors act to initiate the inflame process and release inflammatory mediators
name some examples of inflammatory mediators
cytokine and chemokine including adipokines
ROS, NO and growth factors
