Expression of BRAF V600E mutation in osteoclasts: a murine model of bone erosion in histiocytosis-like disease
OA Version
Citation
Abstract
BRAF is a serine/threonine protein kinase which regulates proliferation, differentiation, and apoptosis of cells as a downstream effector in the RAS-RAF-MEK-ERK/MAPK signaling pathway. Activating mutations in the BRAF gene can induce excessive cell growth and survival and are found in a wide range of human cancers. BRAF mutations are also frequently implicated in Langerhans cell histiocytosis (LCH), including BRAFV600E, which accounts for more than half of all cases. LCH is a rare multisystemic proliferative disorder characterized by the accumulation of hematopoietic cells involved in inflammatory lesions. It is most often diagnosed in children, and its effects can manifest in the skin, bones, lungs, liver, spleen, brain, and more. Bone involvement is a common feature of aggressive forms of the disease, often presenting as osteolytic lesions in the skull and long bones which contribute to generalized and extensive bone loss causing pain, disability, and generally poor prognosis. It is known that this bone erosion is caused by osteoclasts, which are multinuclear cells of hematopoietic origin that specialize in bone resorption, but the precise transcriptional mechanisms of osteoclast activation and regulation are poorly understood. Researchers have demonstrated success in characterizing some multisystemic phenotypes of LCH such as neurodegeneration in animal models, and others have reported models which exhibit bone erosions but have not been studied in the context of BRAF mutations and osteoclast involvement. To this end, we have developed a potential model of multisystemic LCH-like disease in mice that express BRAFV600E—the most common mutation found in LCH patients—in osteoclasts and other myeloid cells that express cathepsin K, a lysosomal cysteine protease integral to the bone remodeling and resorption process. These mice exhibit pathological phenotypes of the skin, bone, and oral and ocular cavities which share some similarities with the clinical presentations of multisystemic LCH in pediatric patients. While our laboratory is currently pursuing a detailed characterization of multisystemic disease using this model, the studies presented here share a focus on investigating BRAFV600E mutant bone and osteoclast phenotypes specifically, as well as elucidating potential molecular mechanisms of their formation and function which may underlie LCH-like pathologies.