Furthermore, it could be noted that deletions affecting 22q13 has been described in two of three reported karyotypes from osteoid osteomas. Available data thus indicate that a candidate target gene for osteoblastoma development may reside in the long arm of chromosome 22. In support of this, one of the aggressive tumors investigated here displayed homozygous deletions of three neighboring regions in 22q12. ZNRF3 and KREMEN1 are negative regulators of Wnt CYM 50260 signaling transduction. Wnt normally acts through different pathways to regulate cell proliferation, cell polarity and cell fate during embryogenesis and adult tissue homeostasis. The different Wnt signaling pathways include the canonical and the non-canonical pathways, the former is also known as the beta-catenin-dependent pathway. In this pathway, cytoplasmic BDY TR-X, SE beta-catenin is constantly phosphorylated leading to ubiquitination and degradation when Wnt is absent. In contrast, when Wnt protein is present it assembles its receptors – the Frizzled family of receptors and various co-receptors including the LDL receptor-related proteins 5 and 6 – which in turn prevents phosphorylation and degradation of beta-catenin. Stabilized beta-catenin will accumulate and translocate to the nucleus to form complexes with transcription factors and activate Wnt target gene expression. The Wnt/beta-catenin pathway regulates, among other things, bone mass and aberrations in this pathway has been found in e.g. osteodegenerative conditions and osteosarcoma. To adjust and restrict Wnt signaling activity there are several negative regulators of this pathway. ZNRF3 encodes a cell-surface transmembrane ubiquitin ligase which reduces Wnt signals by promoting degradation of Frizzled and LRP6 receptors. In absence of ZNRF3, membrane levels of Wnt receptors increase and this enhances Wnt signaling through both the canonical and non-canonical pathways. KREMEN1 is a transmembrane receptor that inhibits the Wnt pathway by forming a ternary complex with Dickkopf1 and LRP5/6. When assembled, this complex is removed from the plasma membrane by endocytosis, thereby blocking Wnt signaling through LRP5/6. Taken together, both loss of ZNRF3 and KREMEN1 would theoretically result in increased accumulation of beta-catenin that will translocate to the nucleus and activate Wnt target gene expression. In line with this, loss of ZNRF3 has been shown to result in accumulation of betacatenin and loss of KREMEN1 has been implicated in increased bone formation. Here, we hypothesized that if loss of genes such as ZNRF3 and KREMEN1 and subsequent activation of beta-catenin is important for osteoblastoma development we would find high expression levels of genes activated by Wnt/beta-catenin in these tumors.