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Increased osteoclastogenesis in mice lacking the carcinoembryonic antigen-related cell adhesion molecule 1.

Heckt T, Bickert T, Jeschke A, Seitz S, Schulze J, Ito WD, Zimmermann W, Amling M, Schinke T, Horst AK, Keller J - PLoS ONE (2014)

Bottom Line: Assessing the expression of all members of the murine Ceacam family in bone tissue and marrow, we found CEACAM1 and CEACAM10 to be differentially expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts.In line with these findings, we detected accelerated osteoclastogenesis in Ceacam1-deficient bone marrow cells, while osteoblast differentiation, as determined by mineralization and alkaline phosphatase assays, was not affected.Therefore, our results provide in vivo and in vitro evidence for a physiologic role of CEACAM1 in the regulation of osteoclastogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

ABSTRACT
Alterations in bone remodeling are a major public health issue, as therapeutic options for widespread bone disorders such as osteoporosis and tumor-induced osteolysis are still limited. Therefore, a detailed understanding of the regulatory mechanism governing bone cell differentiation in health and disease are of utmost clinical importance. Here we report a novel function of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a member of the immunoglobulin superfamily involved in inflammation and tumorigenesis, in the physiologic regulation of bone remodeling. Assessing the expression of all members of the murine Ceacam family in bone tissue and marrow, we found CEACAM1 and CEACAM10 to be differentially expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts. While Ceacam10-deficient mice displayed no alteration in structural bone parameters, static histomorphometry demonstrated a reduced trabecular bone mass in mice lacking CEACAM1. Furthermore, cellular and dynamic histomorphometry revealed an increased osteoclast formation in Ceacam1-deficient mice, while osteoblast parameters and the bone formation rate remained unchanged. In line with these findings, we detected accelerated osteoclastogenesis in Ceacam1-deficient bone marrow cells, while osteoblast differentiation, as determined by mineralization and alkaline phosphatase assays, was not affected. Therefore, our results provide in vivo and in vitro evidence for a physiologic role of CEACAM1 in the regulation of osteoclastogenesis.

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Decreased trabecular bone mass in 6-month-old mice lacking Ceacam1.(A) Von Kossa staining of non-decalcified spine sections from controls (Ceacam1+/+, Ceacam10+/+) and Ceacam1- or Ceacam10-deficient mice (Ceacam1-/-, Ceacam10-/-). Histomorphometric quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume), trabecular number (Tb.N.), trabecular thickness (Tb.Th.) and trabecular separation (Tb.Sp.). All bars represent mean ± SD (n = 5 mice per group). Asterisks indicate statistically significant differences (p<0.05).
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pone-0114360-g002: Decreased trabecular bone mass in 6-month-old mice lacking Ceacam1.(A) Von Kossa staining of non-decalcified spine sections from controls (Ceacam1+/+, Ceacam10+/+) and Ceacam1- or Ceacam10-deficient mice (Ceacam1-/-, Ceacam10-/-). Histomorphometric quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume), trabecular number (Tb.N.), trabecular thickness (Tb.Th.) and trabecular separation (Tb.Sp.). All bars represent mean ± SD (n = 5 mice per group). Asterisks indicate statistically significant differences (p<0.05).

Mentions: As this observation pointed towards a specific role of CEACAM1 and CEACAM10 in the regulation of bone remodeling, we next applied non-decalcified bone histology in mice lacking the respective genes. Von Kossa staining of spine sections from 6-month-old mice demonstrated a reduced bone mass in Ceacam1-deficient mice compared to WT controls, whereas no alteration could be detected in mice lacking CEACAM10 (Fig. 2A). These findings were confirmed by static histomorphometry, which demonstrated Ceacam1-deficient mice exhibit decreased trabecular bone volume accompanied by a reduction in trabecular number and an increase in trabecular separation (Fig. 2B). In contrast, none of these parameters were altered in mice lacking CEACAM10. In order to analyze whether the observed phenotype is also detectable in younger mice, we additionally performed static histomorphometry of 3-month-old mice. Spine sections of Ceacam1-deficient mice were characterized by a significantly reduced trabecular bone mass accompanied by reduced trabecular numbers (S2 Figure), similar to what was observed in 6-month-old animals. In addition, 3-month-old mutant animals displayed a reduced trabecular thickness and increased trabecular separation (S2 Figure). To address the question whether the lack of Ceacam1 not only affects skeletal architecture in vertebrae, but also long bones, we finally performed histomorphometry of non-decalcified tibia sections and µCT-scanning of femora derived from Ceacam1-deficient mice. While we found a decreased trabecular bone volume accompanied by a decrease in trabecular numbers in the tibiae of mutant animals (Fig. 3A), cortical thickness and mean diameter were unaltered in the femora of Ceacam1-deficient mice (Fig. 3B).


Increased osteoclastogenesis in mice lacking the carcinoembryonic antigen-related cell adhesion molecule 1.

Heckt T, Bickert T, Jeschke A, Seitz S, Schulze J, Ito WD, Zimmermann W, Amling M, Schinke T, Horst AK, Keller J - PLoS ONE (2014)

Decreased trabecular bone mass in 6-month-old mice lacking Ceacam1.(A) Von Kossa staining of non-decalcified spine sections from controls (Ceacam1+/+, Ceacam10+/+) and Ceacam1- or Ceacam10-deficient mice (Ceacam1-/-, Ceacam10-/-). Histomorphometric quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume), trabecular number (Tb.N.), trabecular thickness (Tb.Th.) and trabecular separation (Tb.Sp.). All bars represent mean ± SD (n = 5 mice per group). Asterisks indicate statistically significant differences (p<0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260834&req=5

pone-0114360-g002: Decreased trabecular bone mass in 6-month-old mice lacking Ceacam1.(A) Von Kossa staining of non-decalcified spine sections from controls (Ceacam1+/+, Ceacam10+/+) and Ceacam1- or Ceacam10-deficient mice (Ceacam1-/-, Ceacam10-/-). Histomorphometric quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume), trabecular number (Tb.N.), trabecular thickness (Tb.Th.) and trabecular separation (Tb.Sp.). All bars represent mean ± SD (n = 5 mice per group). Asterisks indicate statistically significant differences (p<0.05).
Mentions: As this observation pointed towards a specific role of CEACAM1 and CEACAM10 in the regulation of bone remodeling, we next applied non-decalcified bone histology in mice lacking the respective genes. Von Kossa staining of spine sections from 6-month-old mice demonstrated a reduced bone mass in Ceacam1-deficient mice compared to WT controls, whereas no alteration could be detected in mice lacking CEACAM10 (Fig. 2A). These findings were confirmed by static histomorphometry, which demonstrated Ceacam1-deficient mice exhibit decreased trabecular bone volume accompanied by a reduction in trabecular number and an increase in trabecular separation (Fig. 2B). In contrast, none of these parameters were altered in mice lacking CEACAM10. In order to analyze whether the observed phenotype is also detectable in younger mice, we additionally performed static histomorphometry of 3-month-old mice. Spine sections of Ceacam1-deficient mice were characterized by a significantly reduced trabecular bone mass accompanied by reduced trabecular numbers (S2 Figure), similar to what was observed in 6-month-old animals. In addition, 3-month-old mutant animals displayed a reduced trabecular thickness and increased trabecular separation (S2 Figure). To address the question whether the lack of Ceacam1 not only affects skeletal architecture in vertebrae, but also long bones, we finally performed histomorphometry of non-decalcified tibia sections and µCT-scanning of femora derived from Ceacam1-deficient mice. While we found a decreased trabecular bone volume accompanied by a decrease in trabecular numbers in the tibiae of mutant animals (Fig. 3A), cortical thickness and mean diameter were unaltered in the femora of Ceacam1-deficient mice (Fig. 3B).

Bottom Line: Assessing the expression of all members of the murine Ceacam family in bone tissue and marrow, we found CEACAM1 and CEACAM10 to be differentially expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts.In line with these findings, we detected accelerated osteoclastogenesis in Ceacam1-deficient bone marrow cells, while osteoblast differentiation, as determined by mineralization and alkaline phosphatase assays, was not affected.Therefore, our results provide in vivo and in vitro evidence for a physiologic role of CEACAM1 in the regulation of osteoclastogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

ABSTRACT
Alterations in bone remodeling are a major public health issue, as therapeutic options for widespread bone disorders such as osteoporosis and tumor-induced osteolysis are still limited. Therefore, a detailed understanding of the regulatory mechanism governing bone cell differentiation in health and disease are of utmost clinical importance. Here we report a novel function of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a member of the immunoglobulin superfamily involved in inflammation and tumorigenesis, in the physiologic regulation of bone remodeling. Assessing the expression of all members of the murine Ceacam family in bone tissue and marrow, we found CEACAM1 and CEACAM10 to be differentially expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts. While Ceacam10-deficient mice displayed no alteration in structural bone parameters, static histomorphometry demonstrated a reduced trabecular bone mass in mice lacking CEACAM1. Furthermore, cellular and dynamic histomorphometry revealed an increased osteoclast formation in Ceacam1-deficient mice, while osteoblast parameters and the bone formation rate remained unchanged. In line with these findings, we detected accelerated osteoclastogenesis in Ceacam1-deficient bone marrow cells, while osteoblast differentiation, as determined by mineralization and alkaline phosphatase assays, was not affected. Therefore, our results provide in vivo and in vitro evidence for a physiologic role of CEACAM1 in the regulation of osteoclastogenesis.

Show MeSH
Related in: MedlinePlus