TY - JOUR
T1 - RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk
AU - Najafova, Zeynab
AU - Liu, Peng
AU - Wegwitz, Florian
AU - Ahmad, Mubashir
AU - Tamon, Liezel
AU - Kosinsky, Robyn Laura
AU - Xie, Wanhua
AU - Johnsen, Steven A.
AU - Tuckermann, Jan
N1 - Funding Information:
Acknowledgements The authors thank H. Saito, H. Taipaleenmäki, and K. Jähn for invaluable assistance and support at initial steps of mouse experiments. Moreover, we are grateful to T. Bellido for providing us with Tg(Dmp1-cre)1Btm mice. We are thankful also to N. Molitor for mouse genotyping and S. Baumgart for assistance with mouse experiments. We wish to acknowledge the NGS Integrative Genomics Core Unit at the University Medical Center Göttingen for performing the sequencing. This work was funded by the Dorothea Schlözer program at the University of Göttingen (to ZN); the German Ministry for Science and Education (BMBF) and Agence Nationale de la Recherche-funded iBONE consortium [01KU1401A] (to SAJ); and the German Research Foundation (DFG) [JO 815/3-1] (to SAJ), [TU220/14-1], Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma [CRC1149 C02 INST 492-2] (to JT).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2021/2
Y1 - 2021/2
N2 - The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblast differentiation in vivo. RNF40 expression is essential for early stages of lineage specification, but is dispensable in mature osteoblasts. Paradoxically, while osteoblast-specific RNF40 deletion led to impaired bone formation, it also resulted in increased bone mass due to impaired bone cell crosstalk. Loss of RNF40 resulted in decreased osteoclast number and function through modulation of RANKL expression in OBs. Mechanistically, we demonstrate that Tnfsf11 (encoding RANKL) is an important target gene of H2B monoubiquitination. These data reveal an important role of RNF40-mediated H2B monoubiquitination in bone formation and remodeling and provide a basis for exploring this pathway for the treatment of conditions such as osteoporosis or cancer-associated osteolysis.
AB - The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblast differentiation in vivo. RNF40 expression is essential for early stages of lineage specification, but is dispensable in mature osteoblasts. Paradoxically, while osteoblast-specific RNF40 deletion led to impaired bone formation, it also resulted in increased bone mass due to impaired bone cell crosstalk. Loss of RNF40 resulted in decreased osteoclast number and function through modulation of RANKL expression in OBs. Mechanistically, we demonstrate that Tnfsf11 (encoding RANKL) is an important target gene of H2B monoubiquitination. These data reveal an important role of RNF40-mediated H2B monoubiquitination in bone formation and remodeling and provide a basis for exploring this pathway for the treatment of conditions such as osteoporosis or cancer-associated osteolysis.
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U2 - 10.1038/s41418-020-00614-w
DO - 10.1038/s41418-020-00614-w
M3 - Article
C2 - 32901120
AN - SCOPUS:85090469110
SN - 1350-9047
VL - 28
SP - 700
EP - 714
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 2
ER -