The primary cause of OA is still unknown, which hampers the development of adequate drugs. Because the disease progresses very slowly, the clinical development of therapeutics is difficult as clinical trials would take a long time to complete, making the process extremely expensive. Therefore, the pharmaceutical industry has a keen interest in biomarkers of disease progression, which can be used to select patients for clinical trials.

Epidemiological studies have shown that genetic factors play an important role in OA, especially in patients who develop the disease in multiple joints. In this group, the contribution of genetic factors is estimated at 70%. Genetic research at LUMC is focused on patients with multiple joints affected and a family history of OA. Such research requires the study of patients enriched for genetic effects such as can be observed in patients that are affected in multiple joints at a relatively young age. Because OA is so common in the elderly population, starting out in this elderly group would be like searching for the proverbial needle in the haystack.

The CMSB approach is directed by two main questions: which genes cause OA and are these genes also involved in disease progression? CMSB is interested in common OA, not rare subtypes of the disease. Genetic and molecular epidemiological studies are targeting three groups:

• Young patients (< 40 years) from families affected by OA.
• Middle aged patients (40 - 65 years) with at least one brother or sisters affected by the disease, the so-called sib-pairs.
• General population, through large scale cohorts (e.g. the ERGO study )

Sib-pairs
Within CMSB, the focus is on group 2, the sib-pairs. Two routes are pursued here. In the first, genome scans are performed to localize the genes of interest, which will subsequently be identified. The other route involves testing candidate genes on their presence in this group. As it is clear that OA is connected to processes in the cartilage, genes associated with cartilage formation and metabolism are investigated. The stability of the cartilage matrix might be important; therefore genes related to collagen type II are considered candidate genes for further study.

Associated factors
Another starting point is inflammation. Even though inflammation is not considered to be the primary cause of OA, as it is in rheumatoid arthritis, cytokines are thought to play a role in the progression of the disease, once the cartilage has been damaged. Also important are factor connected to bone metabolism, skeletal formation, general metabolism and overweight and thymus disorders. The latter cause crystalline formations in the cartilage, which could be a trigger for OA.

Biomarkers
To identify biomarkers for disease progression, large numbers of blood and urine samples of patients are tested on the presence of antibodies against fragments of the degraded cartilage matrix. A major problem in OA research is that cartilage samples are not available for study. This is where the multidisciplinary character of CMSB comes in. With so many techniques and expertise areas present, there are ample means to deal with these samples in new ways, in order to maximize the chances of getting useful information.

The main objectives of CMSB are to substantially increase the knowledge on the genetic and molecular background of OA and to identify molecular markers of disease progression. These markers should be applicable in epidemiological studies, to ensure that they can be used for comparing individuals. Once these have been identified, the development of new therapeutics can really get off the ground.

Association studies with radiological characteristics of OA are performed in a cohort (N=1500) of the ERGO study, linkage and association studies are performed in subjects from this cohort study and their sibling pairs (N=270) and in the GARP study (N=400), a prospective study of the LUMC in both clinically and radiologically affected sibling pairs.

1. Meulenbelt I, Bijkerk C, Beekman M, Lakenberg N, Droog S, Duijn CM van, Breedveld FC, and Slagboom PE (2004). Genome wide scan for loci predisposing to familial early onset generalised Osteoarthritis; linkage to the chromosome 2q area. Submitted.
2. Meulenbelt I, Seymour AB, Nieuwland M, Huizinga TW, Duijn CM van, Slagboom PE (2004). Association of the interleukin-1 gene cluster with radiographic signs of osteoarthritis of the hip. Arthritis Rheum Apr;50(4):1179-86
3. Bijkerk C, Houwing-Duistermaat JJ, Valkenburg HA, Meulenbelt I, Hofman A, Breedveld FC, Pols HAP, Duijn CM van, Slagboom PE (1999). Heritabilities of radiological osteoarthritis in peripheral joints and of disc degeneration of the spine. Arthritis Rheum 42(8):1729-1735
4. Meulenbelt I, Bijkerk C, Wildt SCM de, Miedema HS, Breedveld FC, Pols HAP, Hofman A, Duijn CM van, Slagboom PE (1999). Haplotype analysis of three polymorphisms of the COL2A1 gene and associations with generalised radiological osteoarthritis. Ann Hum Genet 63: 393-400
5. Meulenbelt I, Bijkerk C, Breedveld FC, Slagboom PE (1997). Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia. J Med Genet 34: 1024-1027