Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone
- University of Pennsylvania, United States
- Children's Hospital of Philadelphia, United States
- The University of Texas Health Science Center at San Antonio, United States
Abstract
Colony stimulating factor 1 (Csf1) is an essential growth factor for osteoclast progenitors and an important regulator for bone resorption. It remains elusive which mesenchymal cells synthesize Csf1 to stimulate osteoclastogenesis. We recently identified a novel mesenchymal cell population, marrow adipogenic lineage precursors (MALPs), in bone. Compared to other mesenchymal subpopulations, MALPs expressed Csf1 at a much higher level and this expression was further increased during aging. To investigate its role, we constructed MALP-deficient Csf1 CKO mice using AdipoqCre. These mice had increased femoral trabecular bone mass, but their cortical bone appeared normal. In comparison, depletion of Csf1 in the entire mesenchymal lineage using Prrx1Cre led to a more striking high bone mass phenotype, suggesting that additional mesenchymal subpopulations secrete Csf1. TRAP staining revealed diminished osteoclasts in the femoral secondary spongiosa region of Csf1 CKOAdipoq mice, but not at the chondral-osseous junction nor at the endosteal surface of cortical bone. Moreover, Csf1 CKOAdipoq mice were resistant to LPS-induced calvarial osteolysis. Bone marrow cellularity, hematopoietic progenitors, and macrophages were also reduced in these mice. Taken together, our studies demonstrate that MALPs synthesize Csf1 to control bone remodeling and hematopoiesis.
Data availability
Pre-aligned scRNA-seq matrix files were acquired from previously published dataset GEO GSE145477 and snRNA-seq matrix files were from GSE176171 (mouse), human scRNA-seq matrix files were acquired from EMBL-EBI E-MTAB-9139 (human).All data are available as source data files with submission.
-
Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment.NCBI Gene Expression Omnibus, GSE145477.
-
A single-cell atlas of human and mouse white adipose tissue.NCBI Gene Expression Omnibus, GSE176171.
Article and author information
Author details
Funding
National Institute on Aging (R01AG069401)
- Ling Qin
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR078650)
- Ling Qin
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R00AR067283)
- Nathanial Dyment
National Institute on Aging (R01AG045040)
- Jean X Jiang
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 animal work performed in this report was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Pennsylvania under Protocol 806887. University Laboratory Animal Resources (ULAR) of the University of Pennsylvania is responsible for the procurement, care, and use of all university-owned animals as approved by IACUC. Animal facilities in the University of Pennsylvania meet federal, state, and local guidelines for laboratory animal care and are accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.
Copyright
© 2023, Zhong 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.
Metrics
-
- 2,039
- views
-
- 314
- downloads
-
- 30
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone
eLife 12:e82112.
https://doi.org/10.7554/eLife.82112
Further reading
-
- Cancer Biology
- Cell Biology
Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
