Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis and bone mass
- Hospital for Special Surgery, United States
- First Affiliated Hospital of Xiamen University, China
- Weill Cornell, United States
- The University of Texas Health Science Center at San Antonio, United States
Abstract
M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages and osteoclasts. Tissue-resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in the bone marrow produce M-CSF to maintain myeloid homeostasis. Here, we found that Adipoq-lineage progenitors but not mature adipocytes in bone marrow or in peripheral adipose tissue, are a major cellular source of M-CSF, with these Adipoq-lineage progenitors producing M-CSF at levels much higher than those produced by osteoblast lineage cells. Deficiency of M-CSF in bone marrow Adipoq-lineage progenitors drastically reduces the generation of bone marrow macrophages and osteoclasts, leading to severe osteopetrosis in mice. Furthermore, the osteoporosis in ovariectomized mice can be significantly alleviated by the absence of M-CSF in bone marrow Adipoq-lineage progenitors. Our findings identify bone marrow Adipoq-lineage progenitors as a major cellular source of M-CSF in bone marrow and reveal their crucial contribution to bone marrow macrophage development, osteoclastogenesis, bone homeostasis and pathological bone loss.
Data availability
The current manuscript does not contain sequencing data.The Source Data files for figures have been submitted.
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Connecting the Dots: Resolving the Bone Marrow Niche HeterogeneityBroad Institute Single Cell Portal SCP1248.
Article and author information
Author details
Funding
National Institutes of Health (AR078212,AR068970,AR071463)
- Baohong Zhao
National Institutes of Health (AR075585)
- Matthew B Greenblatt
National Institutes of Health (AG045040)
- Jean X Jiang
Tow Foundation (Rosensweig Genomics Center at the Hospital for Special Surgery)
- Baohong Zhao
Welch Foundation (AQ-1507)
- Jean X Jiang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were approved by Institutional Animal Care and Use Committee of the Hospital for Special Surgery and Weill Cornell Medical College (protocol numbers: 2016-0001 and 0004).
Copyright
© 2023, Inoue 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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Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis and bone mass
eLife 12:e82118.
https://doi.org/10.7554/eLife.82118
Further reading
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Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.
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- Medicine
Background:
Identification of individuals with prediabetes who are at high risk of developing diabetes allows for precise interventions. We aimed to determine the role of nuclear magnetic resonance (NMR)-based metabolomic signature in predicting the progression from prediabetes to diabetes.
Methods:
This prospective study included 13,489 participants with prediabetes who had metabolomic data from the UK Biobank. Circulating metabolites were quantified via NMR spectroscopy. Cox proportional hazard (CPH) models were performed to estimate the associations between metabolites and diabetes risk. Supporting vector machine, random forest, and extreme gradient boosting were used to select the optimal metabolite panel for prediction. CPH and random survival forest (RSF) models were utilized to validate the predictive ability of the metabolites.
Results:
During a median follow-up of 13.6 years, 2525 participants developed diabetes. After adjusting for covariates, 94 of 168 metabolites were associated with risk of progression to diabetes. A panel of nine metabolites, selected by all three machine-learning algorithms, was found to significantly improve diabetes risk prediction beyond conventional risk factors in the CPH model (area under the receiver-operating characteristic curve, 1 year: 0.823 for risk factors + metabolites vs 0.759 for risk factors, 5 years: 0.830 vs 0.798, 10 years: 0.801 vs 0.776, all p < 0.05). Similar results were observed from the RSF model. Categorization of participants according to the predicted value thresholds revealed distinct cumulative risk of diabetes.
Conclusions:
Our study lends support for use of the metabolite markers to help determine individuals with prediabetes who are at high risk of progressing to diabetes and inform targeted and efficient interventions.
Funding:
Shanghai Municipal Health Commission (2022XD017). Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212501). Shanghai Municipal Human Resources and Social Security Bureau (2020074). Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR4006). Science and Technology Commission of Shanghai Municipality (22015810500).
