Tal1 regulates osteoclast differentiation through suppression of the master regulator of cell fusion DC-STAMP

Bone is a dynamic tissue that is constantly renewed all through life by the activity of mainly osteoblasts and osteoclasts. An imbalance of these cell types leads to skeletal diseases. Several disorders of the bone tissue are known like osteoporosis, osteopetrosis, rheumatoid arthritis, and also multiple myeloma and metastatic cancer. Bone fractures caused by osteoporosis are a life threatening event that puts more than 70 million people worldwide at risk and is also a considerable economic burden. For this reason, intensive research is aimed to reconstruct the signalling events and the transcriptional network driving osteoclast differentiation. Osteoclasts are resorbing mineralized bone matrix and their function is critical for normal skeletal growth and remodelling. The origin of the osteoclasts are hematopoietic stem cells (HSC). Hematopoietic precursors of the myeloid lineage undergo cell fusion and form multinucleated osteoclasts. The differentiation is largely dependent on the initiation and maintenance of a specific pattern of gene expression; upon cytokine stimulation several signalling pathways and downstream transcription factors are activated.

We show that Tal1 is expressed in osteoclasts precursor cells and mature osteoclasts. We demonstrate that Tal1 influences osteoclast specific genes, is present on the promoters of these genes and most important Tal1 negatively influences osteoclastogenesis. Thus, suggesting Tal1 as a repressor in osteoclast differentiation because it regulates genes important for cell fusion. The identification of Tal1 as a factor involved in cell fusion has an impact on the understanding of osteoclast associated diseases like osteoporosis or giant cell carcinoma.