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Osteoarthritis

Osteoarthritis is the most common disease of the joints for which the prevalence significantly increases with age. Clinical symptoms are pain, stiffness of the joints, whereas, radiographic characteristics of Osteoarthritis are degeneration of articular cartilage and remodelling of the bone. Our research aims at the identification of mechanisms that affect the integrity of the cartilage making it prone to the onset and/or the progression of OA. Especially it will be investigated which genes, gene products together with biochemical parameters may be detected either in blood or urine that may provide biomarkers for the ongoing OA process.

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In order to perform the research on osteoarthritis we have been collected different (patient) populations. These populations include early onset generalized OA families, late onset OA patients and their affected siblings (GARP study) and a cohort of random subjects of the population in which we have assessed the extent of radiographic signs of OA in hand, knee, hip and spine (The Rotterdam study). In part of the latter study we have additionally collected sibling pairs. Specifically candidate genes are investigated encoding components of the extracellular matrix of the cartilage and factors involved in the inflammatory response of cartilage to degradation. Genome wide scans will be performed in order to identify new, unknown OA genes.

By applying genetic approaches to the GARP-study (linkage and association analyses) and early onset OA families (exome sequencing), two novel OA susceptibility genes in a pathway; DIO2 [1] & DIO3 [2] were discovered as well as a compelling high impact mutation in TNFRSF11B encoding OPG [3]. oa researchTo elucidate underlying mechanisms of identified OA pathways in humans and to fill the gap towards clinical translation (Figure 1, left), a novel innovative tailored functional genomic research line was created. By applying several model systems, established in this functional genomic pipeline, mechanistic insight of the discovered DIO2 OA risk allele [4-6] and the high impact mutation in TNFRSF11B [3] with respect to OA was assessed. The results with respect to TNFRSF11B are currently being exploited to test agents that counteract the deleterious OA effect and to support a patent application. Internationally, the functional genomic expertise is recognized and applied in most recent high impact papers reporting on compelling OA gene discoveries (e.g. ALDH1A2 [7], NCOA3 [8]).

To address the biomarker impediment in OA (Figure 1, right), we have, next to conventional biomarkers research [9-13], focussed on exploring the potency of -omic derived OA biomarkers in articular cartilage and blood to respectively assess pathophysiological processes [14-16] and allow classification of OA patients with clinical relevant ROC[14]. To allow in-vivo non-invasive method to assess joint destruction we developed high field interleaved proton / sodium scanning protocol (7T-MRI). Together these lines of research are embedded within national and international research grants.

The research is performed in close collaboration with the Department of Orthopaedics, Rheumatology, and Pathology (LUMC) and is financed by the Dutch Arthritis Association, The Netherlands Organisation of Scientific Research and the industry.

 

References

  1. Meulenbelt I, Min JL, Bos S, Riyazi N, Houwing-Duistermaat JJ, van der Wijk HJ, Kroon HM, Nakajima M, Ikegawa S, Uitterlinden AG, van Meurs JB, van der Deure WM, Visser TJ, Seymour AB, Lakenberg N, van der Breggen R, Kremer D, van Duijn CM, Kloppenburg M, Loughlin J, and Slagboom PE (2008) Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum Mol Genet 17 (12):1867-1875
  2. Meulenbelt I, Bos SD, Chapman K, van der Breggen R, Houwing-Duistermaat JJ, Kremer D, Kloppenburg M, Carr A, Tsezou A, Gonzalez A, Loughlin J, and Slagboom PE (2011) Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility. Ann Rheum Dis 70 (1):164-167
  3. Ramos YF, Bos SD, van der Breggen R, Kloppenburg M, Ye K, Lameijer EW, Nelissen RG, Slagboom PE, and Meulenbelt I (2014) A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis. Ann Rheum Dis
  4. Bos SD, Bovee JV, Duijnisveld BJ, Raine EV, van Dalen WJ, Ramos YF, van der Breggen R, Nelissen RG, Slagboom PE, Loughlin J, and Meulenbelt I (2012) Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. Ann Rheum Dis 71 (7):1254-1258
  5. Bomer N, den HW, Ramos YF, Bos SD, van der Breggen R, Lakenberg N, Pepers BA, van Eeden AE, Darvishan A, Tobi EW, Duijnisveld BJ, van den Akker EB, Heijmans BT, van Roon-Mom WM, Verbeek FJ, van Osch GJ, Nelissen RG, Slagboom PE, and Meulenbelt I (2014) Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis. Ann Rheum Dis
  6. Bomer N, Cornelis FM, Ramos YF, den HW, Storms L, van der Breggen R, Lakenberg N, Slagboom PE, Meulenbelt I, and Lories RJ (2014) The effect of forced exercise on knee joints in Dio2-/- mice: type II iodothyronine deiodinase-deficient mice are less prone to develop OA-like cartilage damage upon excessive mechanical stress. Ann Rheum Dis
  7. Styrkarsdottir U, Thorleifsson G, Helgadottir HT, Bomer N, Metrustry S, Bierma-Zeinstra S, Strijbosch AM et al (2014) Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat Genet 46 (5):498-502
  8. Evangelou E, Kerkhof HJ, Styrkarsdottir U, Ntzani EE, Bos SD, Esko T, Evans DS et al (2014) A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. Ann Rheum Dis 73 (12):2130-2136
  9. Meulenbelt I, Kloppenburg M, Kroon HM, Houwing-Duistermaat JJ, Garnero P, Hellio Le Graverand MP, Degroot J, and Slagboom PE (2006) Urinary CTX-II levels are associated with radiographic subtypes of osteoarthritis in hip, knee, hand, and facet joints in subject with familial osteoarthritis at multiple sites: the GARP study. Ann Rheum Dis 65 (3):360-365
  10. Meulenbelt I, Kloppenburg M, Kroon HM, Houwing-Duistermaat JJ, Garnero P, Hellio-Le Graverand MP, Degroot J, and Slagboom PE (2007) Clusters of biochemical markers are associated with radiographic subtypes of osteoarthritis (OA) in subject with familial OA at multiple sites. The GARP study. Osteoarthritis Cartilage 15 (4):379-385
  11. Bos SD, Kloppenburg M, Suchiman E, van BE, Slagboom PE, and Meulenbelt I (2009) The role of plasma cytokine levels, CRP and Selenoprotein S gene variation in OA. Osteoarthritis Cartilage 17 (5):621-626
  12. Meulenbelt I, Bos SD, Kloppenburg M, Lakenberg N, Houwing-Duistermaat JJ, Watt I, de Craen AJ, van Duijn CM, and Slagboom PE (2010) Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study. Arthritis Rheum 62 (4):1119-1126
  13. Valdes AM, Meulenbelt I, Chassaing E, Arden NK, Bierma-Zeinstra S, Hart D, Hofman A, Karsdal M, Kloppenburg M, Kroon HM, Slagboom EP, Spector TD, Uitterlinden AG, van Meurs JB, and Bay-Jensen AC (2014) Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis. Osteoarthritis Cartilage 22 (5):683-689
  14. Ramos YF, Bos SD, Lakenberg N, Bohringer S, den Hollander WJ, Kloppenburg M, Slagboom PE, and Meulenbelt I (2014) Genes expressed in blood link osteoarthritis with apoptotic pathways. Ann Rheum Dis 73 (10):1844-1853
  15. Ramos YF, den HW, Bovee JV, Bomer N, van der Breggen R, Lakenberg N, Keurentjes JC, Goeman JJ, Slagboom PE, Nelissen RG, Bos SD, and Meulenbelt I (2014) Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAK study. PLoS ONE 9 (7):e103056
  16. den Hollander W, Ramos YF, Bos SD, Bomer N, van der Breggen R, Lakenberg N, de Dijcker WJ, Duijnisveld BJ, Slagboom PE, Nelissen RG, and Meulenbelt I (2014) Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches. Ann Rheum Dis 73 (12):2208-2212