Cindy Boer

180 | Chapter 4.1 Notably, we identified another new total hip replacement- and hand osteoarthritis-as- sociated signal located in such a transcription factor, the TEAD1 gene, indicating a com- mon molecular pathway underlying both signals. TEAD1 functions in the Hippo signal- ling pathway and is transcriptionally regulated by the YAP1 and TAZ protooncogene proteins, which are involved in mechanosensing and mechanotransduction[54, 55]. Mechanoadaptation of articular cartilage is an important factor in osteoarthritis [56, 57]. Two of the likely effector genes have bone remodelling, immune response and inflammatory links. Activation of T-cells can lead to osteoclastogenesis and bone re- sorption by influencing the expression of TNFSF11 (TNF Superfamily Member 11)[58]. TNFSF11 encodes receptor activator of nuclear factor kappa-β ligand (RANKL) , a cy- tokine that has been linked to inflammatory bone remodelling in rheumatoid arthritis, with increased TNFSF11 levels associated with worsening arthritis severity[59, 60] and a well-established role in osteoclastogenesis[61] . FBN2 (fibrillin 2) encodes fibrillin2, a glycoprotein that forms microfibrils in the extracellular matrix and has a major role during early morphogenesis. Fibrillins potently regulate pathways of the immune re- sponse, inflammation and tissue homeostasis[62], are important in bone remodelling and regulate local availability of BMP and TGFα[62]. Mutations in FBN2 cause contrac- tual arachnodactyly[63]. Three genes have a neurological connection. Both C2orf40 and TSEN15 are involved in central nervous system development. Augurin, the protein encoded by C2orf40 (also called ECRG4 ), is involved in central nervous system development in an- imal models[64] and shows association with neuropathologic features of Alzheimer’s disease and related dementias in humans[65]. TSEN15 belongs to a family of proteins (t-RNA splicing endonucleases) that have been found to be mutated in patients with pontocerebellar hypoplasia and microcephaly, indicating a role of the gene in brain development[66].The last gene CUX1 (Cut like homeobox 1) is a transcription factor involved with brain neuronal differentiation and synaptogenesis[67]. Increased CUX1 expression may stimulate cell motility and proliferation[68]. Cux1 expression during developing limb was observed at chondrogenic interzones suggesting a regulatory role in joint formation[69]. The five remaining genes have varied biological functions. COL2A1 (Collagen Type II Alpha 1 Chain) encodes for an essential structural component of cartilage and is important for joint formation and bone growth. A wide spectrum of diseases are as- sociated with COL2A1 including cartilage and bone abnormalities, such as spondyloepi- metaphyseal dysplasia and Kniest dysplasia[70, 71]. SNAP47 (Synaptosome Associat-