thanks for your comment

my point of view is:

Myth: The more one uses one’s joints, the faster they wear

out.

Reality: OA is not a disease of “wear and tear.” Regular (but

not high impact) joint use is benefi cial and necessary for the

health of joints lined with synovium. The cartilage needs

motion to maintain nutrition. Weight-bearing exercise improves

the circulation of blood to the joints because it allows fl uid to

pass through the synovium. Exercise also facilitates lymphatic

drainage, thereby expediting the clearance of oxidative products.

In contrast, the lack of joint motion leads to cartilage atrophy,

a predecessor to OA (Sutton et al. 2001; Lane et al. 1986;

Roos and Dahlberg 2005).

Myth: Infl ammation has little role in the pathophysiology of

OA.

Reality: The classic fi ndings of joint infl ammation are not a cardinal

sign of OA. However, as the disease progresses, synovitis

develops. This is manifested as the joint warmth that is detected

in many patients who have advanced OA of the knee. Synovial

effusions are intermittent in OA, but often develop after overuse

of the joint in a patient with advanced degenerative changes.

Patients with OA do not always notice or complain of

joint swelling, but joint effusions are now recognized with

increasing frequency due to the broader use of magnetic resonance

imaging and ultrasound. The classic description of

infl ammation includes heat, redness, pain, swelling, and loss

of function. The more modern understanding of infl ammation

is that it occurs at a cellular and subcellular level. Many

of the same mechanisms present in rheumatoid arthritis and

other types of arthritis also occur in OA, albeit to a lesser

degree (Bonnet and Walsh 2005).

this comment is adopted from :A Clinician’s Pearls and Myths in Rheumatology, text book 2009.chapter43,osteoarthritis,by Nancy E. Lane and Roy D. Altman

springer. i will upload this chapter 4 you

it is degenerative disorder of the catilage with joints and more imprtant is there that ischemmic reperfusion phenomenon in disturbed..... and more medial spaae is reduced coz more brader condyles and more wt bearing during walking and climbing stairs....... so i prefer to improve space with knee skin traction.....then cartilage will be rebuilded..and for cartilage u need to give protrein supplement..

It has been proposed that lthe progression of OA to advanced states is driven by atheromatous vascular disease. They support the hypothesis that subchondral bone ischaemia contributes to joint degeneration. So, statins can slow progression of established OA.

Baker GF, Walsh P and Mulhall KJ (2010): Statins: A potential role in the management of osteoarthritis. Joint Bone Spine J. ARTICLE IN PRESS

It has been proposed that lthe progression of OA to advanced states is driven by atheromatous vascular disease. They support the hypothesis that subchondral bone ischaemia contributes to joint degeneration. So, statins can slow progression of established OA.

Baker GF, Walsh P and Mulhall KJ (2010): Statins: A potential role in the management of osteoarthritis. Joint Bone Spine J. ARTICLE IN PRESS

great posts Abdallah!

This is a new concept for me, and one that I will definatly be investigating in the future, thank you.

If the proposed metabollic cause is of haemodynamic origin, has there been higher incedence of OA reported in people with say diabetes (problems with microvascular system)....accounting for that people with diabetes are typacally more obese and at higher risk for athersclerosis

Obesity not only alter biomechanics it also plays an important role in inflammation

adipose tissue is considered as endocrine organ

it releases many pro-inflammatory and inflammatory cytokine that destroy cartilage

Great post abdullah

Recently,,,,,,,,Nerve Growth factor is considered a cause of pain and disability in osteoarthritis,,,,,,Tanezumab is a monoclonal antibody against nerve growth factor. It was developed by Pfizer as a treatment for pain.It is under trial.

should explain why sometimes patients have seemingly inretractable pain that is not always related to severity and clinical picture of OA.... Is the Tanezumab able to target established 'new' nociceptive growth within AO jnts or prevent nerve factor from working and hens getting worse in the future?

challenges in managemnent of OA knee pain:

**********************multiple sites for pain origin

*Sources of knee pain:

1- Inflamed synovium.

2- Microfracture of subchondral bone.

3- Periosteum stretching by osteophytes.

4- Venous congestion in intraosseous compartment.

5- Joint distension.

6- Muscle spasm.

7- Bursal inflammations.

8- Altered joint mechanics.

9- Mental depression.

************chronicity of pain is due to:

--peripheral sensitization: loss of free nerve endings,,,deviant pattern of innervation and loss of proper tissue sensory feedback

-----central sensitization: facilitation of pain transmission after peripheral injury

*********************** many mediators are involved in pain production and inflammation and there's no drug uptil now targets all mediators

thanks again for your reply Abdallah, they are always in great detail! sorry if my questions are annoying you haha.....

I understand the multifaceted nature of pain esp. with OA but I suppose I was asking if you knew (in a simple explination) the mode of action for this drug within osteoarthritic joints. I was not implying that I thought that seemingly inretractable pain was due to facilitation of spinothalamic tracts and neurons within its neuronal pool alone. It was like a 'ah ha!' moment when you rightly pointed out the pressence of growth factors and its role in peripheral and synaptic senstivity and was curious about the role this drug has on retarding some of this process.

Not at all

this drug still under trial

wait untill we get more details about it

Early stages of osteoarthritis are clinically silent

so, when patient complains,,,this means that degree of OA changes is more than we expect

also, degree of pain may be out of proportion of OA degree, and it differs from 1 patient to another

PAIN THRESHOLD IS THE CAUSE

do you agree with such conclusions?????

Thanks Dr. Allam for these Valuable posts.

regarding this point>>>>> (Inflammation has little role in the pathophysiology of OA.)

>how can we consider the changes that occur to the cartilage itself (enzymatic destruction & other chemicals) and what trigger it ?

& is there any proved role for Heredity ?

seems VERY plausable to me, and resonnates with my (limited) experience!!

However as your great list above points out there are alot of differant eitiology why someone with OA will experience pain. Do you also think it would be plausable that a patient with mild to modarate OA changes can experience substantial pain and disability from inflammed synovium, jnt distension, muscle spasm, bursitis etc? but i supose then these changes a probably least likely caused by DJD then??

Abdallah, could you please write a small reference list of some great texts for me to purchase?

Dr alaa

recently

osteoarthritis is considered inflammatory disease rather than degenerative disease

Dear adam i will send you an email containing some valuable references as a gift

plz send to me your e mail

as regard genetics

Genetic predisposition

A genetic disposition to OA has been clear since it was first

reported by Kellgren and coworkers [1] that generalized

nodal OA was twice as likely to occur in first-degree relatives

as in control individuals. Twin pair and family risk studies have

indicated that there is a significantly higher concordance for

OA between monozygotic twins than between dizygotic

twins, and that the hereditable component of OA may be in

the order of 50% to 65% [2]. However, because of the

prevalence of OA in the general population and extensive

clinical heterogeneity, the precise genetic contribution to the

pathogenesis of OA has been difficult to analyze. Moreover, it

is clear that multiple genetic factors can contribute to the

incidence and severity of OA, and that these may differ

according to specific joint (hand, hip, knee, or spine), sex, and

race. There is also evidence, given the variety of candidate

genes that predispose to OA, that there may be an additive

effect of individual genes in the development of disease [3].

Several candidate genes encoding proteins of the extracellular

matrix of the articular cartilage have been associated

with early-onset OA [4]. In addition to point mutations in type

II collagen [5], inherited forms of OA may be caused by mutations

in several other genes that are expressed in cartilage,

including those encoding types IV, V, and VI collagens, as

well as cartilage oligomeric matrix protein (COMP) [6].

Candidate genes for OA have also been identified that are

not structural proteins. Among such candidates are the

secreted frizzled-related protein 3, asporin, and von Willebrand

factor genes [7,8]. In follow-up studies it has been

reported that the asporin, frizzled-related protein 3, and von

Willebrand factor genes have now been found not to

replicate in large Caucasian meta-analyses and that the

association with growth differentiation factor (GDF)-5 in

Caucasians has been confirmed in larger meta-analyses

[9-12]. Finally, evidence from mouse models indicates that

genetic disorders affecting the architecture of subchondral

bone can cause OA. Mice with a null mutation of the latent

transforming growth factor (TGF)-β binding protein-3, which

regulates the activation of TGF-β, developed both osteosclerosis

and OA [13]. In addition, a recent report

demonstrated that a genetic defect of type I collagen resulted

in rapidly progressive OA in a mouse model [14].

In recent population studies, genome-wide linkage scans

have highlighted several specific genes involved in disease

risk [15]. Chromosome 2q was positive in several scans,

suggesting that this chromosome is likely to harbor one or

more susceptibility genes. Two IL-1 genes (IL1α and IL1β)

and the gene encoding IL-1 receptor antagonist (IL1RN),

located on chromosome 2q13 within a 430-kilobase genomic

fragment, have been shown to associate with the

development of primary knee, but not hip, OA [16]. IL1RN

haplotype variants have also been shown to associate with

radiographic severity of the OA [17]. Recently, a genomewide

association scan has identified a cyclo-oxygenase

(COX)-2 variant involved in risk for knee OA [18]. These

genetic associations of genes such as IL1α, IL1β, IL1RN,

and COX2 underscore the potential role of inflammatory

pathways in the pathogenesis of knee OA.

Review

Developments in the scientific understanding of osteoarthritis

Steven B Abramson and Mukundan Attur Arthritis Research & Therapy 2009, 11:227

read plz for more knowledge about OA risks

Abdallah, that would be fantastic!! thanks mate!!

[email protected]

'An important emerging theme in osteoarthritis is a broadening of focus from a disease of cartilage to one of the ‘whole joint’.' So simple its superb! another 'ah ha' moment haha

I am not the expert to share you and I do not know why Dr Abdallah El-Sayed Allam have facebooked me to comment on your participation. Well I am impressed by your comprehensive knowledge on the subject and I have learned a lot specially from the role of statins and I am not sure are they beneficial because o their anti-atheromatous or their well known anti-inflammatory effects. Any way Ihave recently come across a recent publication on the role of genetics in the aetiology and the age of onset at which OA might occur. Osteoarthritis (OA) has a considerable hereditary component and is considered to be a polygenic disease. Data derived from genetic analyses and genome-wide screening of individuals with this disease have revealed a surprising trend: genes associated with OA tend to be related to the process of synovial joint development. Mutations in these genes might directly cause OA. In addition, they could also determine the age at which OA becomes apparent, the joint sites involved, the severity of the disease and how rapidly it progresses.

.Nat Rev Rheumatol. 2012 Jan 10. doi: 10.1038/nrrheum.2011.199.

yes OA is the disease of whole joint structures as it involves not only cartilage also subchondral bone,,menisci,,synovium as following:

Local production and release of pro-inflammatory cytokines e.g. (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)) from synovial lining cells, macrophages and chondrocytes play a central role in the pathogenesis of OA. IL-1β and TNF-α production activates the transcription factor nuclear factor-kappa B (NF-κB) in chondrocytes. Once activated, NF-κB translocates into the nucleus, where it induces the expression of distinct subsets of genes encoding inflammatory, apoptotic and extracellular matrix (ECM) degrading enzymes. NF-κB activates the expression of matrix degrading enzymes such as matrix metalloproteinases (MMPs) and enzymes responsible for production of prostaglandins (that is, cyclooxygenase-2 (COX-2)) leading to enhanced degradation of the ECM and induction of pain. Additionally, in articular chondrocytes, NF-κB stimulates the production of pro-inflammatory catabolic cytokines, which induce apoptosis through activation of the proapoptotic enzyme caspase-3 and cleavage of the deoxyribonucleic acid repair enzyme; poly adenosine diphosphate-ribose polymerase (PARP).

Nitric oxide also plays a catabolic role in the development of OA and mediates the inflammatory response. It is involved in the degradation of matrix, inhibits the synthesis of both collagen and proteoglycans, and helps to mediate apoptosis.

These degrading and degenerative processes gradually lead to an imbalance between cartilage catabolism and anabolism ending in cartilage destruction with pathologic changes in other joint structures which in turn participate in the progression of the disease process.

Osteophytes: is an endochondral ossificatin .Osteoarthritic knees with large osteophytes are more likely to progress than knees without them, the relation of osteophytes to progression is accounted for, in part, by their relation to malalignment which causes disease progression.

Subchondral bone sclerosis: with disruption of blood flow which reduces nutrient diffusion to articular cartilage in OA. Also, ischaemia in subchondral bone may produce osteocyte death, bone resorption and articular damage in OA.

Calcification of articular cartilage (both hyaline and meniscal) is a well recognized feature of OA and current evidence suggests that it contributes directly to joint degeneration

Bone marrow lesions (BMLs): include bone marrow edema and cysts are associated with progressive knee cartilage degeneration and treatment of BMLs reduces progression of cartilage degeneration.

Synovitis: Although OA is often classed as a non-inflammatory disease, a variable degree of synovitis can be observed in OA. This synovitis is characterized by papillary hyperplasia of the synovial membrane, proliferation of blood vessels and infiltration with mononuclear cells (predomi¬nantly T-cells). It has been hypothesized that the synovium might play an important role in the pathogenesis of OA by the induction of various pro- and anti-inflammatory agents.

i wanna to tell you that Prof. Dr Tarek Alatrozy is one of the great prof. i met.He has an excellent teaching approaches i always learn from him and i hope to be one of his good students

for my dear prof. dr tarek

Statins and their anti-inflammatory effects:it is possible that these agents act on the intrinsic cholesterol content in cell membranes.

interfere with leukocyte attachment to endothelial cells. This prevents the subsequent escape by the endothelial cell from the vasculature.

Inhibition of the formation of focal adhesion

complexes (foci for transmembrane adhesion molecules) is thought to be due to the effect of statins on members of the Rho family.

interfere with the chemoattractant action of monocyte chemotactic protein-1 (MCP-1).

The ability of statins to reduce the expression of a number of inflammatory cytokines is likely due to their inhibition of NF-B activation in monocytes or endothelial cells that have been exposed to inflammatory stimuli. NF-B is a transcriptional regulator of more than 40 inflammatory genes.

It has been proposed that lthe progression of OA to advanced states is driven by atheromatous vascular disease. They support the hypothesis that subchondral bone ischaemia contributes to joint degeneration. So, statins can slow progression of established OA.

from reference mentioned above

approaches for OA TTT

I want to know about monosodium glutamate model

It presents in many types of food

it plays a role in obesity

it may be cytotoxic

I want model for osteoarthritis but sudcutaneous

Sorry subcutaneous

Alll these post threads are very educative. Thx, nice reading.