Osteocytes regulate senescence of bone and bone marrow
- Shanghai Sixth People's Hospital, China
- University of Western Australia, Australia
- University of Chinese Academy of Sciences, China
Abstract
The skeletal system contains a series of sophisticated cellular lineages arisen from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), that determine the homeostasis of bone and bone marrow. Here we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit 𝛼 (DTA) in dentin matrix protein 1 (DMP1) positive osteocytes, we demonstrated that partial ablation of DMP1 positive osteocytes caused severe sarcopenia, osteoporosis and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocytes reduction altered mesenchymal lineage commitment resulting in impairment of osteogenesis and induction of osteoclastogensis. Single cell RNA sequencing further revealed that hematopoietic lineage was mobilized towards myeloid lineage differentiation with expanded myeloid progenitors, neutrophils and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteoprogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulation of lineage cell specifications in bone and bone marrow through mediation of senescence.
Data availability
ScRNA-Seq and RNA-seq data have been deposited into GEO repository with accession codes GSE202516 and GSE202356 respectively. Source data have been deposited in Dryad.
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Osteocytes regulate skeletal senescence during developmentNCBI Gene Expression Omnibus, GSE202516.
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Osteocytes regulate skeletal senescence during developmentNCBI Gene Expression Omnibus, GSE202356.
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Osteocytes regulate senescence of bone and bone marrowDryad Digital Repository, doi:10.5061/dryad.5tb2rbp6k.
Article and author information
Author details
Funding
National Natural Science Foundation of China (82002339)
- Junjie Gao
National Natural Science Foundation of China (81820108020)
- Changqing Zhang
Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002)
- Changqing Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mei Wan, Johns Hopkins University, United States
Ethics
Animal experimentation: All mice experiments were approved by the Animal Care and Use Committee of Shanghai Sixth People's Hospital (Permit number: 2021-0935, 2021-0936). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Version history
- Received: June 29, 2022
- Preprint posted: July 18, 2022 (view preprint)
- Accepted: October 27, 2022
- Accepted Manuscript published: October 28, 2022 (version 1)
- Version of Record published: November 21, 2022 (version 2)
Copyright
© 2022, Ding et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Osteocytes regulate senescence of bone and bone marrow
eLife 11:e81480.
https://doi.org/10.7554/eLife.81480
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