Transcriptional Control of Steroid Biosynthesis Genes in the Drosophila Prothoracic Gland by Ventral Veins Lacking and Knirps.

Specialized endocrine cells produce and release steroid hormones that govern development, metabolism and reproduction. In order to synthesize steroids, all the genes in the biosynthetic pathway must be coordinately turned on in steroidogenic cells. In Drosophila, the steroid producing endocrine cells are located in the prothoracic gland (PG) that releases the steroid hormone ecdysone. The transcriptional regulatory network that specifies the unique PG specific expression pattern of the ecdysone biosynthetic genes remains unknown. Here, we show that two transcription factors, the POU-domain Ventral veins lacking (Vvl) and the nuclear receptor Knirps (Kni), have essential roles in the PG during larval development. Vvl is highly expressed in the PG during embryogenesis and is enriched in the gland during larval development, suggesting that Vvl might function as a master transcriptional regulator in this tissue. Vvl and Kni bind to PG specific cis-regulatory elements that are required for expression of the ecdysone biosynthetic genes. Knock down of either vvl or kni in the PG results in a larval developmental arrest due to failure in ecdysone production. Furthermore, Vvl and Kni are also required for maintenance of TOR/S6K and prothoracicotropic hormone (PTTH) signaling in the PG, two major pathways that control ecdysone biosynthesis and PG cell growth. We also show that the transcriptional regulator, Molting defective (Mld), controls early biosynthetic pathway steps. Our data show that Vvl and Kni directly regulate ecdysone biosynthesis by transcriptional control of biosynthetic gene expression and indirectly by affecting PTTH and TOR/S6K signaling. This provides new insight into the regulatory network of transcription factors involved in the coordinated regulation of steroidogenic cell specific transcription, and identifies a new function of Vvl and Knirps in endocrine cells during post-embryonic development

Giant cell tumour of bone: new treatments in development

Giant cell tumour of bone (GCTB) is a benign osteolytic tumour with three main cellular components: multinucleated osteoclast-like giant cells, mononuclear spindle-like stromal cells (the main neoplastic components) and mononuclear cells of the monocyte/macrophage lineage. The giant cells overexpress a key mediator in osteoclastogenesis: the RANK receptor, which is stimulated in turn by the cytokine RANKL, which is secreted by the stromal cells. The RANK/RANKL interaction is predominantly responsible for the extensive bone resorption by the tumour. Historically, standard treatment was substantial surgical resection, with or without adjuvant therapy, with recurrence rates of 20–56 %. Studies with denosumab, a monoclonal antibody that specifically binds to RANKL, resulted in dramatic treatment responses, which led to its approval by the United States Food and Drugs Administration (US FDA). Recent advances in the understanding of GCTB pathogenesis are essential to develop new treatments for this locally destructive primary bone tumour