Abstract
The transmembrane aminopeptidase CD13 is highly expressed in cells of the myeloid lineage, regulates dynamin-dependent receptor endocytosis and recycling and is a necessary component of actin cytoskeletal organization. Here, we show that CD13-deficient mice present a low bone density phenotype with increased numbers of osteoclasts per bone surface, but display a normal distribution of osteoclast progenitor populations in the bone marrow and periphery. In addition, the bone formation and mineral apposition rates are similar between genotypes, indicating a defect in osteoclast-specific function in vivo. Lack of CD13 led to exaggerated in vitro osteoclastogenesis as indicated by significantly enhanced fusion of bone marrow-derived multinucleated osteoclasts in the presence of M-CSF and RANKL, resulting in abnormally large cells containing remarkably high numbers of nuclei. Mechanistically, while expression levels of the fusion-regulatory proteins dynamin and DC-STAMP1 must be downregulated for fusion to proceed, these are aberrantly sustained at high levels even in CD13-deficient mature multi-nucleated osteoclasts. Further, the stability of fusion-promoting proteins is maintained in the absence of CD13, implicating CD13 in protein turnover mechanisms. Together, we conclude that CD13 may regulate cell–cell fusion by controlling the expression and localization of key fusion regulatory proteins that are critical for osteoclast fusion.
Highlights
The transmembrane aminopeptidase CD13 is highly expressed in cells of the myeloid lineage, regulates dynamin-dependent receptor endocytosis and recycling and is a necessary component of actin cytoskeletal organization
Osteoclastogenesis is a critical process for skeletal growth and development that is tightly regulated by differentiation of myeloid progenitor cells into osteoclasts, which are specialized bone marrow (BM)-derived cells whose major function is bone resorption[1]
We demonstrate that despite a relatively normal distribution of hematopoietic components in bone marrow and periphery[12], bone mass in CD13KO mice is reduced and OC number per bone surface area is increased while bone formation parameters are normal, indicating that in the
Summary
The transmembrane aminopeptidase CD13 is highly expressed in cells of the myeloid lineage, regulates dynamin-dependent receptor endocytosis and recycling and is a necessary component of actin cytoskeletal organization. Osteoclastogenesis is a critical process for skeletal growth and development that is tightly regulated by differentiation of myeloid progenitor cells into osteoclasts, which are specialized bone marrow (BM)-derived cells whose major function is bone resorption[1]. OCs form from committed monocyte progenitors via initial signals provided by two key BM-derived cytokines: macrophage colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL), initiating a highly-organized program of commitment towards terminal differentiation and function[6,7,8] This program requires the precise regulation of the expression of cell–cell fusion proteins that is critical to the generation of functionally active OCs. Despite our current knowledge of events leading to the formation of OCs, understanding the regulation of these processes in homeostatic and pathological conditions is u nclear[9,10,11]. We hypothesize that CD13 is a negative regulator of cell–cell fusion in osteoclastogenesis and potentially, a universal modulator of membrane fusion and is a novel target for therapeutic intervention in pathological conditions mediated by defects in cell–cell fusion
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