Characterizing the role of osteoclasts in the unique marrow fibrosis phenotype of osteoclast-rich severe autosomal recessive osteopetrosis
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Abstract
Osteopetrosis is a rare bone disorder where patients have increased bone density due to decreased number or dysfunction of osteoclasts. Previous research has identified a unique marrow fibrosis phenotype in osteoclast-rich forms of this disease, and we hypothesize that the presence of marrow fibrosis is due to the presence of dysfunctional osteoclasts. Nfatc1 knockout and Clcn7 knockout mice were used to characterize and quantify the marrow fibrosis phenotype via histologic analysis. These models were crossed with Rank knockout mice to investigate the osteoclast dependence of this fibrotic marrow phenotype. Treatment with anti-RANK ligand will be used to further investigate the osteoclast dependence of marrow fibrosis.
Marrow fibrosis is present and quantifiable in Clcn7 and Nfatc1 knockout mice, and we are able to restore hematopoietic marrow in Rank double knockout mouse models where dysfunctional osteoclasts are not present. Pilot studies appear to demonstrate restoration of hematopoeitc marrow elements in Clcn7 and Nfatc1 knockout mice following treatment with anti-RANK ligand.
This study demonstrates the marrow fibrosis is both quantifiable in Clcn7 and Nfatc1 knockout mice, and that hematopoetic marrow can be preserved through genetic deletion of osteoclasts. Hematopoietic marrow can also apparently be restored in Nfatc1 knockout mice through treatment with anti-RANK ligand. These findings provide an understanding of the role of dysfunctional osteoclasts in the marrow fibrotic phenotype of osteoclast-rich osteopetrosis, and lay the foundation for investigation of therapeutic targets.
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2024