CoChat
Sign Up
Cited by 114Bone Metabolism and DiseasesBone health and osteoporosis researchOsteomyelitis and Bone Disorders Research

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

Local Production of Osteoprotegerin by Osteoblasts Suppresses Bone Resorption

Open access
Cawley, Keisha M., Bustamante-Gomez, Nancy Cecile, Guha, Anveshi G., MacLeod, Ryan S., Xiong, Jinhu, Gubrij, Igor, Liu, Yu, Mulkey, Robin, Palmieri, Michela, Thostenson, Jeff D., Goellner, Joseph J., O’Brien, Charles A.·2020·Cell Reports
DOI 10.1016/j.celrep.2020.108052PMC PMC7493998
Open this paper in CoChat — free accountOpen PDF

Abstract

Osteoprotegerin (OPG) inhibits the ability of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) to stimulate the differentiation, activity, and survival of bone-resorbing osteoclasts. Genetic studies in mice show that osteocytes are an important source of RANKL, but the cellular sources of OPG are unclear. We use conditional deletion of Tnfrsf11b, which encodes OPG, from different cell populations to identify functionally relevant sources of OPG in mice. Deletion from B lymphocytes and osteocytes, two cell types commonly thought to supply OPG, has little or no impact on bone mass. By contrast, deletion of Tnfrsf11b from osteoblasts increases bone resorption and reduces bone mass to an extent similar to germline deletion, demonstrating that osteoblasts are an essential source of OPG. These results suggest that, in addition to producing new bone matrix, osteoblasts also play an active role in terminating the resorption phase of the bone remodeling cycle by suppressing RANKL activity.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2020.108052

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1. Deletion of Tnfrsf11b from B Cells Does Not Alter Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by micro-computed tomography (μCT) (n = 6–8). (B) Cancellous bone volume over tissue volume (BV/TV) of femurs and L4 vertebra (n = 6–8). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. The indicated p values were determined by one-way ANOVA. See also Figures S1–S3 and Data S1.
Figure 1. Deletion of Tnfrsf11b from B Cells Does Not Alter Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by micro-computed tomography (μCT) (n = 6–8). (B) Cancellous bone volume over tissue volume (BV/TV) of femurs and L4 vertebra (n = 6–8). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. The indicated p values were determined by one-way ANOVA. See also Figures S1–S3 and Data S1.CC BY-NC-ND · PubMed Central
Figure 2. Deletion of Tnfrsf11b from Mature Osteoblasts and Osteocytes Decreases Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 5–7). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 5–9). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of femoral cortical porosity measured by μCT (n = 5–7). (F) Soluble OPG and RANKL in the serum measured by ELISA (n = 5–10). (G) Tnfrsf11b, Tnfsf11, TRAP, and CTSK mRNA levels in tibial cortical bone (n = 4–9). All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. Cortical thickness and BV/TV values for Tnfrsf11b+/+ and Tnfrsf11b−/− mice are the same as in Figure 1. The indicated p values were determined by one-way ANOVA. See also Figures S1, S3, and S4 and Data S1.
Figure 2. Deletion of Tnfrsf11b from Mature Osteoblasts and Osteocytes Decreases Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 5–7). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 5–9). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of femoral cortical porosity measured by μCT (n = 5–7). (F) Soluble OPG and RANKL in the serum measured by ELISA (n = 5–10). (G) Tnfrsf11b, Tnfsf11, TRAP, and CTSK mRNA levels in tibial cortical bone (n = 4–9). All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. Cortical thickness and BV/TV values for Tnfrsf11b+/+ and Tnfrsf11b−/− mice are the same as in Figure 1. The indicated p values were determined by one-way ANOVA. See also Figures S1, S3, and S4 and Data S1.CC BY-NC-ND · PubMed Central
Figure 3. Deletion of Tnfrsf11b from Osteocytes Results in a Mild Decrease in Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 6–7). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 6–7). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of cortical porosity of femurs measured by μCT (n = 5–7). (F) Tnfrsf11b, Tnfsf11, TRAP, and CTSK mRNA levels in tibial cortical bone (n = 6–8). All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. Cortical thickness, BV/TV, and cortical porosity values for Tnfrsf11b+/+ and Tnfrsf11b−/− mice are the same as in Figures 1 and 2. The indicated p values were determined by one-way ANOVA. See also Figures S1 and S3 and Data S1.
Figure 3. Deletion of Tnfrsf11b from Osteocytes Results in a Mild Decrease in Bone Mass (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 6–7). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 6–7). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of cortical porosity of femurs measured by μCT (n = 5–7). (F) Tnfrsf11b, Tnfsf11, TRAP, and CTSK mRNA levels in tibial cortical bone (n = 6–8). All values are from 5-week-old female mice of the indicated genotypes, and bars are means ± SD. Cortical thickness, BV/TV, and cortical porosity values for Tnfrsf11b+/+ and Tnfrsf11b−/− mice are the same as in Figures 1 and 2. The indicated p values were determined by one-way ANOVA. See also Figures S1 and S3 and Data S1.CC BY-NC-ND · PubMed Central
Figure 4. Osteoblastic Tnfrsf11b Suppresses Resorption in Adult Mice (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 6). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 6). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of cortical porosity of femurs measured by μCT (n = 5–6). (F) Soluble OPG and RANKL in the serum measured by ELISA (n = 6–11). All values are from 4-month-old female mice, and bars are means ± SD. The indicated p values were determined by one-way ANOVA. See also Figures S1, S5, and S6 and Data S1.
Figure 4. Osteoblastic Tnfrsf11b Suppresses Resorption in Adult Mice (A) Cortical thickness in the femur and L4 vertebra measured by μCT (n = 6). (B) Cancellous BV/TV of femurs and L4 vertebra (n = 6). (C) Cross sections of the femoral diaphysis viewed by μCT. Scale bar, 500 μm. (D) μCT images of vertebral cancellous bone. Scale bar, 500 μm. (E) Quantitative analysis of cortical porosity of femurs measured by μCT (n = 5–6). (F) Soluble OPG and RANKL in the serum measured by ELISA (n = 6–11). All values are from 4-month-old female mice, and bars are means ± SD. The indicated p values were determined by one-way ANOVA. See also Figures S1, S5, and S6 and Data S1.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 49 references

Cited by

Sorted by citations

See all 114

Related

Metadata

Authors
Cawley, K. M., Bustamante-Gomez, N. C., Guha, A. G., MacLeod, R. S., Xiong, J., Gubrij, I., Liu, Y., Mulkey, R., Palmieri, M., Thostenson, J. D., Goellner, J. J., & O’Brien, C. A.
Affiliations
  • University of Arkansas for Medical Sciences (US)
  • Central Arkansas Veterans Healthcare System (US)
Corresponding author
O’Brien, Charles A.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-09
Volume
32
Issue
10
Pages
108052
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.108052
PMC
PMC7493998
OpenAlex
W3084164734
Cited by
114
References
49
Citations by year
2026: 15 · 2025: 18 · 2024: 15 · 2023: 20 · 2022: 28 · 2021: 13 · 2020: 5
FWCI
5.35
Type
journal article
Language
en
Update notices
erratum (2025-06-24)
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000294)
  • University of Arkansas for Medical Sciences
  • National Institutes of Health (R01AR049794, P20GM125503)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Keywords
osteoprotegerin, osteoblasts, bone resorption, RANKL, osteocytes, B cells, bone remodeling, conditional gene deletion, bone mass, osteoclasts
MeSH terms
Animals, Cell Differentiation, Humans, Osteoblasts, Osteoclasts, Osteocytes, Bone Remodeling, Mice, Osteoprotegerin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review