الفهرس 
Cartilage Histology and BiochemistryOnly 14 pages are availabe for public view
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Abstract
Osteoarthritis is the most common form of chronic arthritis, and it is a major cause of pain, disability and decreased of quality of life. OA can be clinically described as joint pain and reduced mobility, associated radiographically with JSN, subchondral bone sclerosis and osteophyte formation.
The factors that initiate OA are not well understood, and the course of joint degeneration in OA is variable. There is a disagreement on defining the primary trigger of OA with some animal models pointing towards changes in articular cartilage occurring first, while others suggesting underlying bone changes first.
The close physical relationship between the cartilage and subchondral bone in joints introduced the concept that there is molecular crosstalk between chondrocytes and bone cells (osteoblasts, osteoclasts and osteocytes) and if it exists, the extent to which it may contribute to the progression of OA.
The Wnt pathway involves Wnt proteins which are family of secreted proteins. The Wnt family members are classically divided into canonical and non-canonical pathway components. The Canonical Wnt pathway is activated upon binding of Wnt to a coreceptor complex located at the cell surface, comprising LRP 5/6 and a member of Fz family of proteins. This interaction finally leads to an increase of the intracellular β -catenin levels through inhibition of the β-catenin degradation.
The regulatory mechanisms of canonical Wnt signaling pathway are very complex. This pathway is regulated by several soluble inhibitors such as Dkk-1, sclerostin, and sFRP and some activators as canonical Wnts and Dvl.
Dkk-1 inhibits Canonical Wnt pathway through binding LRP5/6 and Kremen (a receptor that does not transduce intracellular signal) and their complex is internalized, leading to depletion of cell surface from LRP5/6 receptors; which become unavailable for binding the Wnt proteins, resulting in inhibition of the pathway.
Dkk-1 has been suggested to play a role in OA pathogenesis. Its role in human OA has not been explored in detail and its function in OA cartilage destruction is a subject of controversy.
Activation of Wnt signaling by blocking of the Wnt antagonist Dkk-1 leads to increased osteophyte formation suggesting that Wnt activation can induce new bone formation in arthritic joints and also allow the growth of osteophyte.
When invesigators studied cartilage specimens from patients with OA and femoral fractures they found that Dkk-1 expression increased in OA cartilage and correlated with chondrocyte apoptosis as blocking β- catenin increased apoptosis and when Dkk-1 was blocked chondrocyte apoptosis decreased. On contrary other investigators found negative effect of Wnt signaling on cartilage formation and that it activates cartilage degeneration.
Conventional radiography is the golden standard in imaging of OA for diagnosing of knee OA and for grading the severity of the disease. However, it has clear limitations in imaging hyaline cartilage and other soft tissues, which are frequently involved with disease progression over the years. Also plain radiographs have very low sensitivity in indicating minimal cartilage involvement in early disease.
Recently, US has been regarded as a valuable tool in assessment of OA due to its ability to detect and evaluate abnormalities involving hyaline cartilage, synovial fluid and synovial membrane, menisci rapidly with low cost. It allows assessment of OA through early detection and progression of articular cartilage abnormalities and can serve as a good alternative for initial evaluation of OA patients to MRI.
The present study was carried out to find out the relation between serum levels of Dkk-1 and the occurrence of primary O.A in the knee and to find out its relation to disease severity assessed clinically, radiologicaly and sonographicaly.
This study was conducted on patients with primary knee OA, classified into 3 groups, each containing 20 patients with mild (group I), moderate (Group II) and severe (Group III) OA according to Kellgren and Lawrence, (1957) grading with total number 60 patients. Twenty apparently healthy subjects with normal knee X ray who were matched for sex, weight and height were chosen as a control group.
All patients were subjected to full medical history, clinical examination, functional assessment, laboratory investigations including CBC, ESR, ALT, ALP, serum calcium, serum phosphorus, serum create, serum uric acid and FBS. Serum levels of Dkk-1 were measured using ELISA technique. Plain x ray and US were done for the affected knee to assess radiological severity of the disease.
It was the first time to assess serum Dkk-1 levels in relation to the grade of cartilage degeneration severity by using US.
Our study revealed that:
• There was a highly significant decrease in serum Dkk-1 in patients versus the control.
• There was insignificant relation between serum Dkk-1 and either age or BMI.
• There was highly statistical significant decrease in patients of group II and group III versus the control but not group I versus the control.
• There was a statistical significant decrease in Dkk-1 level in patients of group III versus patients of group I, while there was no significant difference between patients of group III versus those of group II or between patients of II and those of group I.
• There was a highly statistical significant decrease in Dkk-1 level with increased functional impairment.
• There was a statistically highly significant decrease in serum Dkk-1 in patients with moderate and severe functional impairment than those with mild functional impairment, while there was no statistical significant difference between serum Dkk-1 in patients with severe and moderate functional impairment.
• There was a statistically highly significant decrease in serum Dkk-1 level with severity of cartilage degeneration at medial and lateral femoral condyle and femoral sulcus.
• There was a statistically significant decrease in serum Dkk-1 in patients with G2 and G3 cartilage degeneration at medial femoral condyle versus G1 while there was a non-significant difference between G3 versus G2.
• There was a statistically highly significant decrease in serum Dkk-1 in patients with G1, 2 and 3 cartilage degeneration at sulcus versus G0, while there was a non-significant difference between G1 versus G2 and G3 or between G2 versus G3.
• There was a statistically highly significant decrease in serum Dkk-1 in patients with G2 versus G0, and a statistically significant decrease in serum Dkk-1 in patients with G1 and G3 versus G0, while there was a non-significant difference between G1 versus G2 and G3 or G 2 versus G3.
• There was a statistically highly significant decrease in Dkk-1 level with increased cartilage score.
• There was statistically highly significant decrease in serum Dkk-1 with increased number of regions with cartilage degeneration.
• There was a negative statistically highly significant correlation between Dkk-1 and clinical, radiological and ultrasonographic findings.
In conclusion: Dkk-1 levels were measured in primary knee OA patients at every stage of the disease and its level was highly significantly lower in advanced stage of the disease compared to the early OA patients according to the degree of radiographic severity. Also Dkk-1 level decreased with increased cartilage degeneration and functional disability. So it seems that proper level of canonical Wnt signaling is essential for cell survival as increased level of Dkk-1 also may derive the induction of chondrocyte apoptosis and OA by blocking β catenin. This may suggest that Dkk-1 can be a useful prognostic tool to reflect the disease severity of primary knee OA.
US is an important imaging tool for assessment of knee OA severity and it is of great value in detecting severity of cartilage degeneration it was associated with x ray findings and functional impairment.