The role of the osteoclast in severe autosomal osteopetrosis
OA Version
Citation
Abstract
Osteopetrosis is a bone disease characterized by increased bone density due to few or abnormal functioning osteoclasts. Many patients with osteopetrosis also present with marrow fibrosis that is likely due to uncoupling of the bone remodeling cycle, however the exact mechanism behind why it occurs is unknown. We hypothesize that the marrow fibrosis in individuals with osteoclast-rich osteopetrosis is caused by osteoclast-derived signals that promote precursor osteoblastic expansion. To explore this, we first characterized the osteopetrotic phenotypes of Nfatc1 knockout, Clcn7 knockout and Slc4a2 knockout mouse models. We found that all three mutations led to marrow fibrosis, however Nfatc1 knockout mice experienced a much more severe form of the disease. To further understand the classification of the stromal cells, we performed immunohistochemistry, CD45- qPCR and cell cultures. In doing so, we identified that the stromal cells in the Nfatc1 knockout model express high levels of osteoblastic genes and are capable of forming mineralized bone nodules, supporting the hypothesis that the stromal cells are pre-osteoblastic. Further experiments are currently underway to identify if this holds true for the Clcn7 and Slc4a2 mutations. To investigate if the stromal cell infiltration was osteoclast dependent, we crossed the Clcn7 knockout and Nfatc1 knockout genotypes with a Rank knockout to eliminate osteoclasts. In doing so, we found that marrow fibrosis was not present at birth of the double knockout mice, substantiating the idea that the fibrosis is osteoclast dependent. Lastly, we treated Nfatc1 knockout and Slc4a2 knockout mice with a RANKL antagonist. From this, we found that through depletion of osteoclasts, marrow fibrosis can be reversed.