| 1. |
- Bostrom, E. A., et al.
(author)
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Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines
- 2015
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Journal article (peer-reviewed)abstract
- Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1 beta (IL-1 beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappa B pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.
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| 2. |
- Holm, Cecilia Koskinen, et al.
(author)
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Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation
- 2016
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 478:1, s. 268-273
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Journal article (peer-reviewed)abstract
- Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRP alpha) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRP alpha mutant mice lacking the cytoplasmic signaling domain of SIRPa. An impaired osteoblastogenesis in SIRP alpha-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPa-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRP alpha-mutant cells. In conclusion, our data suggest that SIRPa signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells.
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| 3. |
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| 4. |
- Kindstedt, Elin, et al.
(author)
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Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
- 2018
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In: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 70:4, s. 508-515
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Journal article (peer-reviewed)abstract
- Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.
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| 5. |
- Kindstedt, Elin, 1991-, et al.
(author)
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CCL11, a novel mediator of inflammatory bone resorption
- 2017
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7:1
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Journal article (peer-reviewed)abstract
- Normal bone homeostasis, which is regulated by bone-resorbing osteoclasts and bone-forming osteoblasts is perturbed by inflammation. Inchronic inflammatory disease with disturbed bone remodelling, e.g. rheumatoid arthritis, patients show increased serum levels of the chemokine eotaxin-1 (CCL11). Herein, we demonstrate an inflammatory driven expression of CCL11 in bone tissue and a novel role of CCL11 in osteoclast migration and resorption. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that expression increased during inflammatory conditions. Osteoclasts did not express CCL11, but the high affinity receptor CCR3 was significantly upregulated during osteoclast differentiation and found to colocalise with CCL11. Exogenous CCL11 was internalised in osteoclast and stimulated the migration of pre-osteoclast and concomitant increase in bone resorption. Our data pinpoints that the CCL11/CCR3 pathway could be a new target for treatment of inflammatory bone resorption.
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| 6. |
- Kindstedt, Elin, et al.
(author)
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Discovery of Innate Lymphoid Cells in Gingivitis and Periodontitis
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Other publication (other academic/artistic)abstract
- AIM: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs can also contribute to inflammatory diseases such as asthma and colitis. We analysed the presence and proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Furthermore, we investigated if ILCs express nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.MATERIALS AND METHODS: We collected gingivitis and periodontitis soft tissue and characterised ILC subsets including RANKL expression in single cell suspensions using flow cytometry. RESULTS: Although not statistically significant, the total number of ILCs detected was twice as many in periodontitis compared to gingivitis. The majority of ILCs, in both conditions, were ILC1s with a 2.5-fold increase of ILC1s in periodontitis compared to gingivitis. Furthermore, we found RANKL expression exclusively expressed on ILC1s.CONCLUSIONS: Our discovery of the presence of ILCs in gingivitis and periodontitis and concomitant expression of RANKL in ILC1 suggest that these cells may be of importance in periodontal disease. In addition, our findings provide new insights into the field of oral immunology.
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| 7. |
- Kindstedt, Elin, et al.
(author)
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Innate lymphoid cells are present in gingivitis and periodontitis
- 2019
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In: Journal of Periodontology. - : Wiley-Blackwell. - 0022-3492 .- 1943-3670. ; 90:2, s. 200-207
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Journal article (peer-reviewed)abstract
- BACKGROUND: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs are also contributors of inflammatory diseases such as asthma and colitis. We analyzed the presence and relative proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Further, we investigated if ILCs express receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.METHODS: We collected gingivitis and periodontitis soft tissue and characterized ILC subsets including RANKL expression in single-cell suspensions using flow cytometry.RESULTS: ILCs were detected both in gingivitis and periodontitis. The majority of ILCs, in both conditions, were ILC1s. Furthermore, RANKL expression was detected on a fraction of the ILC1s.CONCLUSIONS: Our discovery of the presence of ILCs both in gingivitis and periodontitis and concomitant expression of RANKL on a fraction of the ILC1 population suggest that these cells may be of importance in periodontal disease. In addition, our findings provide a new insight into the field of oral immunology.
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| 8. |
- Kindstedt, Elin, et al.
(author)
-
Marginal jawbone loss is associated with onset of rheumatoid arthritis and is related to plasma level of receptor activator of nuclear factor kappa-B-ligand (RANKL)
-
Other publication (other academic/artistic)abstract
- OBJECTIVES: We investigated whether periodontitis, displayed as marginal jawbone loss, preceded onset of symptoms of RA. Furthermore, we analysed plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption and of anti-citrullinated peptide antibodies (ACPA) in pre-symptomatic individuals compared with controls.METHODS: Marginal jawbone levels were measured on dental radiographs from the premolar/molar regions of the jaws of 176 subjects of whom 93 had developed RA. Of these, 47 had documented radiographs predating symptom onset and for 45 of them sex, age and smoking status referents could be matched. The plasma RANKL concentrations were analysed using ELISA. The receiver operating characteristic curve was used to define the cut-off value.RESULTS: Compared with matched referents, bone loss was significantly higher in never-smoking, pre-symptomatic subjects and increasing levels of bone loss was associated with higher risk to develop subsequent RA (hazard ratio=1.06, 95%CI 1.01, 1.11). No association was found in smokers. In the pre- symptomatic RANKL-positive individuals a significantly higher extent of marginal jawbone loss, and those who were both RANKL- and ACPA positive displayed an even more pronounced jawbone loss.CONCLUSIONS: Marginal jawbone loss preceded clinical onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, pre- symptomatic RA-individuals, who were RANKL positive, displayed a significantly higher degree of marginal jawbone loss, particularly in ACPA positive individuals.
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| 9. |
- Kindstedt, Elin, et al.
(author)
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Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Marginal Jawbone Loss Predates the Onset of Rheumatoid Arthritis
- 2017
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In: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 69
-
Journal article (other academic/artistic)abstract
- Background/Purpose: Previous studies have shown a higher incidence of alveolar bone loss in patients with rheumatoid arthritis (RA) and that patients with periodontitis are at a greater risk for developing RA. Periodontitis, displayed as marginal jawbone loss was analysed in individuals prior to symptom onset of RA and related to plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption. Methods: A case-control study performed within the Medical Biobank of Northern Sweden included 232 pre-symptomatic individuals with blood samples donated before symptom onset and 194 controls. A questionnaire on self-assed dental status and smoking status was retrieved. Dental radiographs to evaluate marginal jawbone levels were available from 93 pre-symptomatic individuals (mean age; 56.8 95%CI55.9, 57.7 years and pre-dating time; -5.3 95%CI -12.2, -0.2, 74.2% females) and 83 controls (mean age; 55.5 95%CI54.6, 56.5, 73.5% females) . Of these individuals 45 had radiograph documentations prior to development of RA symptoms and to whom sex, age and smoking status could be matched among the controls. Plasma were analysed for RANKL (BioVendor, Karasek, Czech Republic), and anti-citrullinated peptide antibodies (ACPA) (anti-CCP2 test, Eurodiagnostics, Sweden) from similar time points. Results: Compared to matched controls, total bone loss was significantly higher in never-smokers who developed RA but not in smokers and increasing levels on total jawbone loss was associated with a significantly higher odds to be diagnosed with RA later (OR=1.06, 95%CI 1.01, 1.11). Regardless of smoking status, the number of unaffected teeth did not differ significantly between those who were subsequently diagnosed with RA and their matched controls. In the pre-symptomatic individuals RANKL positive individuals had significantly higher extent of marginal jawbone loss, which was further increased in ACPA positive individuals. Previously documented association between smoking and ageing and marginal jawbone loss was verified. Conclusion: Marginal jawbone loss preceded onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, marginal jawbone loss and plasma RANKL levels were related in the pre-symptomatic individuals particularly in ACPA positive individuals.
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| 10. |
- Kolan, Shrikant, 1983-, et al.
(author)
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Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen
- 2015
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In: PLoS One. - : plos one. - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.
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| 11. |
- Koskinen Holm, Cecilia, et al.
(author)
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Engineering a 3D In Vitro Model of Human Gingival Tissue Equivalent with Genipin/Cytochalasin D
- 2022
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:13
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Journal article (peer-reviewed)abstract
- Although three-dimensional (3D) co-culture of gingival keratinocytes and fibroblasts-populated collagen gel can mimic 3D structure of in vivo tissue, the uncontrolled contraction of collagen gel restricts its application in clinical and experimental practices. We here established a stable 3D gingival tissue equivalent (GTE) using hTERT-immortalized gingival fibroblasts (hGFBs)-populated collagen gel directly crosslinked with genipin/cytochalasin D and seeding hTERT-immortalized gingival keratinocytes (TIGKs) on the upper surface for a 2-week air–liquid interface co-culture. MTT assay was used to measure the cell viability of GTEs. GTE size was monitored following culture period, and the contraction was analyzed. Immunohistochemical assay was used to analyze GTE structure. qRT-PCR was conducted to examine the mRNA expression of keratinocyte-specific genes. Fifty µM genipin (G50) or combination (G + C) of G50 and 100 nM cytochalasin D significantly inhibited GTE contraction. Additionally, a higher cell viability appeared in GTEs crosslinked with G50 or G + C. GTEs crosslinked with genipin/cytochalasin D showed a distinct multilayered stratified epithelium that expressed keratinocyte-specific genes similar to native gingiva. Collagen directly crosslinked with G50 or G + C significantly reduced GTE contraction without damaging the epithelium. In summary, the TIGKs and hGFBs can successfully form organotypic multilayered cultures, which can be a valuable tool in the research regarding periodontal disease as well as oral mucosa disease. We conclude that genipin is a promising crosslinker with the ability to reduce collagen contraction while maintaining normal cell function in collagen-based oral tissue engineering.
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| 12. |
- Koskinen Holm, Cecilia, et al.
(author)
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Successful rehabilitation after multiple severe complications following orthognathic surgery : a case report
- 2023
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In: BMC Oral Health. - : BioMed Central (BMC). - 1472-6831 .- 1472-6831. ; 23:1
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Journal article (peer-reviewed)abstract
- Background. Complications of orthognathic surgery are quite rare, but they cause suffering in affected individuals.The range of complications is broad and includes both hard and soft tissue.Case presentation: We here present a case of a fully healthy woman without signs of impaired healing capacity. Thepatient underwent bimaxillary orthognathic surgery and experienced multiple complications both peri- and postoperatively.During the post operative period, the patient also suffered from soft tissue complications after an orthopaedicinjury. Therefore, we referred the patient to her general practitioner for further medical investigation. Wealso present the result after restorative surgery and endodontic and prosthodontic treatment resulting in a successfulrehabilitation.Conclusion: This case report clearly shows the need for a good collaboration between different odontologicaland medical fields to achieve a good and predictable result. In situations where normal healing processesdo not occur, in-depth analysis must be carried out.Highlights: Orthognathic surgery affects soft and hard tissue which can result in adverse healing and complications.It is of great importance to follow up performed surgery to see late complications. Be restrictive with earlyre-operations when there are signs of necrosis. Always use a multidisciplinary approach when handling complicationsafter surgery.
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| 13. |
- Rosendahl, Sara, et al.
(author)
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CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice
- 2021
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In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 296
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Journal article (peer-reviewed)abstract
- Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C–C chemokine receptor 3 (CCR3) is dramatically upregulated during osteoclastogenesis, but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages derived from adult male CCR3-proficient and CCR3-deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices, and altered mRNA expression of related chemokine receptors and ligands. In addition, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator–related gene, receptor activator of nuclear factor kappa-B ligand, and osteoblast differentiation–associated genes. Microcomputed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the total number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endocortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.
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| 14. |
- Rosendahl, Sara, 1991-
(author)
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Chemokines and bone : lessons from in vitro and in vivo studies
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Bone homeostasis is maintained by the balanced activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Inflammation in the vicinity of bone disturbs the balanced bone remodeling process, which often results in bone loss. The chemokine C-C motif chemokine ligand 11 (CCL11) is associated with several conditions that inflict bone loss and it increases the recruitment and activity of osteoclasts. Osteoclasts express high levels of the CCL11 receptor C-C motif chemokine receptor 3 (CCR3). Although chemokines and chemokine receptors are demonstrated to be involved in both physiological and pathological bone turnover, their roles in skeletal growth, maturation, and bone remodeling are only partially understood. The overarching aim of this thesis was to investigate if CCR3 regulates osteoclast and osteoblast differentiation and function in vitro, and if it affects bone modeling and remodeling in vivo. Furthermore, this project aimed to elucidate the molecular mechanisms by which CCL11 interacts with and affects osteoclasts. In murine cell culture experiments, we identified that CCR3-deficient osteoclasts became larger and had more nuclei compared to CCR3-proficient osteoclasts. This was accompanied by an increased bone resorption activity, although none of the investigated osteoclast-associated genes were affected by the absence of CCR3. On the other hand, CCR3-deficient osteoblasts demonstrated an increased expression of osteoanabolic genes and the crucial osteoclast differentiation factor regulator of nuclear factor kappa B ligand (RANKL). Using micro-computed tomography, we demonstrated that CCR3-deficient adolescent and adult male mice had thinner cortical bones and lower cortical bone volumes compared to CCR3-proficient mice. Interestingly, no skeletal phenotype was detected in female mice. Among juvenile CCR3-deficient mice, neither males nor females showed a skeletal phenotype, which indicates that the observed phenotype in CCR3-deficient adolescent and adult mice was not acquired due to an impaired early bone modeling process. In addition, histomorphometric analyses showed an increased cortical mineral apposition rate in both adolescent and adult male mice, and an increased cortical bone formation in adult male mice, whereas osteoclast numbers and size were not affected in vivo. Advanced microscopy analyses were used to assess the membrane binding and internalization of fluorescent CCL11 in pre-osteoclasts and osteoclasts. We detected that CCL11 was rapidly internalized in pre-osteoclasts, whereas the initial CCL11 interaction in mature osteoclasts mainly involved surface binding to actin-rich protrusions on the cell membrane. Live-cell imaging demonstrated an overall increased cell motility and speed of pre-osteoclasts exposed to CCL11. Using an immunobased array screening of pre-osteoclasts stimulated with CCL11, we also detected alternations in the signaling network of cytoskeletal proteins coupled to cell migration and adhesion. In conclusion, we discovered that the absence of CCR3 regulates both osteoclast and osteoblast differentiation and function in vitro. This was reflected in vivo, since CCR3-deficiency caused a cortical femoral bone phenotype in adolescent and adult male, but not female, mice. Furthermore, we demonstrated that CCL11 increases osteoclast motility and identified that CCL11 regulates cytoskeletal protein signaling in osteoclasts.
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| 15. |
- Rosendahl, Sara, et al.
(author)
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Lack of CCR3 leads to a skeletal phenotype only in male mice
- 2022
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 620, s. 98-104
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Journal article (peer-reviewed)abstract
- We recently showed that adult male mice that lacked the C–C-chemokine receptor 3 (CCR3) exhibited disturbed bone remodeling, which resulted in a cortical bone phenotype of thin femoral cortical bone. However, it remains unknown whether this phenotype would be present during bone modeling, or it affects female mice. Here, we analyzed juvenile and adolescent CCR3-deficient mice to determine when bone modeling was affected in the absence of CCR3 signaling. To investigate whether the CCR3 bone phenotype was sex-related, we analyzed both young female and male mice, and adult females.Micro-computed tomography (μCT) and histomorphometric analyses in adolescent CCR3-deficient male mice revealed reduced cortical bone volume and thickness, and an increase in periosteal mineralization. Interestingly, no skeletal phenotype was observed in adolescent or adult female CCR3-deficient mice. Among juvenile CCR3-deficient mice, neither males nor females showed a skeletal phenotype, which indicated that bone modeling was not affected by the CCR3 deficiency.In summary, adolescent and adult male mice that lacked CCR3 receptors exhibited a cortical phenotype that was not present in female mice, probably due to an estrogen protective mechanism. Based on these and our previous results, we suggest that the importance of CCR3 in cortical bone turnover is related to sex hormones. Because only a few molecules are known to control cortical bone turnover, our novel finding that CCR3 regulated cortical bone thickness only in males suggested that CCR3 is a novel target for controlling cortical bone morphology in male individuals, and perhaps, in post-menopausal women.
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