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

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Local Production of Osteoprotegerin by Osteoblasts Suppresses Bone Resorption

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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
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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.

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Crossref · 10.1016/j.celrep.2020.108052

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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

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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

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