Flavio Nguyen posted an update 3 months ago
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 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 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. Indeed, Wnt/beta-catenin target genes involved in bone metabolism, such as BMP2, BMP4, PTGS2 and MMP16, showed high expression levels in osteoblastoma. In line with this, both membranous and nuclear beta-catenin has been found to be strongly expressed in osteoblastoma. Furthermore, constitutional APC mutations leading to accumulation of beta-catenin is associated with the development of osteoma, a benign bone lesion that shares some morphological features with osteoid osteoma and osteoblastoma. ZNRF3 and KREMEN1 may thus be potential target genes of one of the homozygously deleted regions. Possible targets of the two adjacent, homozygously deleted regions may be MN1 and NF2. MN1 encodes a transcription regulator and was originally identified as a gene disrupted in meningioma and as part of a fusion gene in leukemia. MN1 has been shown to be involved in osteoblast proliferation and differentiation. More specifically, osteoblasts derived from MN1 knock-out mice are defective in osteoblast proliferation, migration, differentiation and mineralization. The skeletal defects of the MN1 knock-out seem to primarily affect cranial skeletal elements while long bones of the appendicular skeleton appear to develop normally. Mutations in NF2 are associated with the autosomal Kinase Inhibitor Library dominant disorder neurofibromatosis type 2. Affected patients primarily develop tumours of the nervous system, including schwannomas, meningiomas and ependymomas. NF2 has not been specifically associated with bone formation. Instead, in patients with craniofacial dysmorphism and concomitant deletions affecting NF2, the deletions have been shown to encompass also the MN1 gene, supporting the role of MN1 in human craniofacial development. The protein product of NF2 is also known to inhibit many signaling pathways at the membrane and in the nucleus, including the Wnt/beta-catenin pathway. The effectiveness of clinical pain management can often be improved by co-administering agents that leverage different pharmacological mechanisms or by combining multiple pharmacologies within a single molecule.