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Cited by 47Bone Metabolism and DiseasesImmune Response and InflammationBone health and osteoporosis research

Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

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Ding, Peng, Tan, Qiyuan, Wei, Zhanying, Chen, Qiyu, Wang, Chun, Qi, Luyue, Wen, Li, Zhang, Changqing +1 more·2022·Bone Research
DOI 10.1038/s41413-022-00210-3PMC PMC9142495
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Abstract

Toll-like receptors (TLRs) play pivotal roles in inflammation and provide important links between the immune and skeletal systems. Although the activation of TLRs may affect osteoclast differentiation and bone metabolism, whether and how TLRs are required for normal bone remodeling remains to be fully explored. In the current study, we show for the first time that TLR9−/−mice exhibit a low bone mass and low-grade systemic chronic inflammation, which is characterized by the expansion of CD4+T cells and increased levels of inflammatory cytokines, including TNF α, RANKL, and IL1 β. The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss. Importantly, TLR9 deletion alters the gut microbiota, and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9−/−mice. Furthermore, through single-cell RNA sequencing, we identified myeloid-biased hematopoiesis in the bone marrow of TLR9−/−mice and determined that the increase in myelopoiesis, likely caused by the adaptation of hematopoietic stem cells to systemic inflammation, also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9−/−mice. Thus, our study provides novel evidence that TLR9 signaling connects the gut microbiota, immune system, and bone and is critical in maintaining the homeostasis of inflammation, hematopoiesis, and bone metabolism under normal conditions.

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Cited by

Sorted by citations

Authors
Ding, P., Tan, Q., Wei, Z., Chen, Q., Wang, C., Qi, L., Wen, L., Zhang, C., & Yao, C.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Second Affiliated Hospital of Soochow University (CN)
Corresponding author
Zhang, Changqing
ORCID
Venue
Bone Research
Publisher
Springer Science and Business Media LLC
Published
2022-05-27
Volume
10
Issue
1
Pages
42-42
ISSN
  • 2095-4700 (ISSN-L)
  • 2095-6231
DOI
10.1038/s41413-022-00210-3
PMC
PMC9142495
OpenAlex
W4281741064
Cited by
47
References
11
Citations by year
2026: 9 · 2025: 13 · 2024: 12 · 2023: 9 · 2022: 4
FWCI
3.10
Type
journal article
Language
en
Update notices
correction (2022-07-07)
Open access
Licence
Locations
  • Bone Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Natural Science Foundation of Shanghai (21ZR1448600, 2018YFC1106300, 81820100820)
  • National Natural Science Foundation of China (81820100820, 81400855, 81372845)
  • Science and Technology Commission of Shanghai Municipality (14pj1407200)
  • National Institutes of Health (4r01dk092882-05)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-092882, R01DK126809, P30DK045735, R01DK130318)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
TLR9, osteoclastogenesis, bone loss, gut microbiota, dysbiosis, myelopoiesis, hematopoietic stem cells, CD4+ T cells, RANKL, TNF-α, IL-1β, bone remodeling, bone metabolism

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