Genetics in osteoarthritis

In general, genetics play a weak role in the development of osteoarthritis.

The strongest genetic association is with FRZB – also known as “frizzled-related-protein-3”  – which is associated with hip osteoarthritis in women. Why might that be?

FRZB is an antagonist to (counter balances) the effects of the WNT pathway.

When there is a slight mutation at the gene coding for FRZB, the FRZB that the body produces is slightly defective – it does not do quite so good a job at inhibiting or counter-balancing WNT. Therefore, whatever WNT does – when FRZB is defective, WNT will do more of it. Got that?

What does WNT do? One thing it does is activate NF-kB.

So defective FRZB => more WNT activity => more NF-kB activity => hip osteoarthritis in women.

The first publication:

June, 2004

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.

Very brief summary of the abstract

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder.

[Long discussion of gene mapping and statistical associations.]

Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.

The second publication:

Invest Ophthalmol Vis Sci. 2009 Oct 29.

The pathogenic role of the canonical Wnt pathway in age-related macular degeneration.

Zhou T, Hu Y, Chen Y, Zhou K, Zhang B, Gao G, Ma JX.

Biochemistry, Zhongshan University, Guangzhou, China.

Summary of the abstract

PURPOSE. Our previous studies showed that the Wnt signaling pathway is activated in the retina and retinal pigment epithelium of animal models of age-related macular degeneration (AMD) and diabetic retinopathy (DR). The purpose of this study is to investigate the role of the canonical Wnt pathway in pathogenesis of these diseases.

The activation of the Wnt pathway significantly up-regulated expression of VEGF, NF-kB and TNF-alpha. Further, Ad-S37A induced ROS generation in a dose-dependent manner. Wnt3a also induced a 2-fold increase of ROS generation. Intravitreal injection of Ad-S37A up-regulated expression of VEGF, ICAM-1, NF-kappaB, TNF-alpha and increased protein nitrotyrosine levels in the retina of normal rats.

CONCLUSION. Activation of the canonical Wnt pathway is sufficient to induce retinal inflammation and oxidative stress and plays a pathogenic role in AMD and DR

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