CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis

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 phenot...

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Autores principales:	Mallika Ghosh, Tomislav Kelava, Ivana Vrhovac Madunic, Ivo Kalajzic, Linda H. Shapiro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c76605703dea4829b0ced176c41a2067
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spelling	oai:doaj.org-article:c76605703dea4829b0ced176c41a20672021-12-02T16:53:01ZCD13 is a critical regulator of cell–cell fusion in osteoclastogenesis10.1038/s41598-021-90271-x2045-2322https://doaj.org/article/c76605703dea4829b0ced176c41a20672021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90271-xhttps://doaj.org/toc/2045-2322Abstract 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.Mallika GhoshTomislav KelavaIvana Vrhovac MadunicIvo KalajzicLinda H. ShapiroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mallika Ghosh Tomislav Kelava Ivana Vrhovac Madunic Ivo Kalajzic Linda H. Shapiro CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
description	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.
format	article
author	Mallika Ghosh Tomislav Kelava Ivana Vrhovac Madunic Ivo Kalajzic Linda H. Shapiro
author_facet	Mallika Ghosh Tomislav Kelava Ivana Vrhovac Madunic Ivo Kalajzic Linda H. Shapiro
author_sort	Mallika Ghosh
title	CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
title_short	CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
title_full	CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
title_fullStr	CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
title_full_unstemmed	CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis
title_sort	cd13 is a critical regulator of cell–cell fusion in osteoclastogenesis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c76605703dea4829b0ced176c41a2067
work_keys_str_mv	AT mallikaghosh cd13isacriticalregulatorofcellcellfusioninosteoclastogenesis AT tomislavkelava cd13isacriticalregulatorofcellcellfusioninosteoclastogenesis AT ivanavrhovacmadunic cd13isacriticalregulatorofcellcellfusioninosteoclastogenesis AT ivokalajzic cd13isacriticalregulatorofcellcellfusioninosteoclastogenesis AT lindahshapiro cd13isacriticalregulatorofcellcellfusioninosteoclastogenesis
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CD13 is a critical regulator of cell–cell fusion in osteoclastogenesis

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