33 results on '"Bravenboer N"'
Search Results
2. Expression of RANKL in breast cancer tissue in patients with fibrous dysplasia/McCune-Albright syndrome
- Author
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Meier, M.E., Hagelstein-Rotman, M., Majoor, B.C.J., Geels, R.E.S., Appelman-Dijkstra, N.M., and Bravenboer, N.
- Published
- 2023
- Full Text
- View/download PDF
3. Expression of RANKL in breast cancer tissue in patients with fibrous dysplasia/McCune-Albright syndrome
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Meier, M E, Hagelstein-Rotman, M, Majoor, B C J, Geels, R E S, Appelman-Dijkstra, N M, Bravenboer, N, Laboratory Specialized Diagnostics & Reseach, Amsterdam Gastroenterology Endocrinology Metabolism, AMS - Tissue Function & Regeneration, and AMS - Ageing & Vitality
- Subjects
GNAS ,Histology ,Breast cancer ,Physiology ,Endocrinology, Diabetes and Metabolism ,RANKL ,Fibrous dysplasia ,McCune -Albright syndrome - Abstract
BACKGROUND: In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), mosaic mutations in the GNAS gene lead to locally abnormal bone turnover. Additionally, patients with FD/MAS, particularly with thoracic lesions, have an increased risk for breast cancer. Development and progression of breast cancer has been associated with expression of Receptor Activator of NF-κB ligand (RANKL) in mammary tissue, and due to the GNAS mutation, RANKL is systemically increased in patients with FD/MAS. Yet it is unknown whether breast cancer in FD/MAS is also dependent on RANKL. We hypothesized that the GNAS mutation might induce RANKL overproduction and an oncogenic niche in mammary tissue, and examined RANKL expression in breast cancer tissue of patients with FD/MAS compared to controls.METHODS: Nine patients with FD/MAS and breast cancer were included and clinical data were retrieved. Patients were matched to controls with breast cancer without FD/MAS based on age and tumor type. Three pregnant breast cancer patients were included as positive controls. Immunohistochemical detection of RANKL was performed on formalin-fixed paraffin-embedded breast cancer specimens. Staining intensity was classified as weak, moderate or intense. The area of positive RANKL staining divided by the total ductal-lobular area was assessed (positive area percentage, PAP). Number of patients with RANKL expression was compared between FD/MAS and control group by chi-square (χ 2) test, the PAP by Mann-Whitney U test (MWU). RESULTS: RANKL expression was observed in 3 patients with FD/MAS (38 %), mainly in healthy tissue, and none of the control patients (χ 2p = 0.055). The FD/MAS group demonstrated considerably more intense staining than the control group, comparable to positive controls. The median PAP was 0.64 % (range 0.14-2.04 %) in the 3 FD/MAS patients with RANKL expression, 0.01 % (Q1-Q3: 0.0003-0.514 %) in the entire FD/MAS group, 0.006 % (Q1-Q3: 0.001-0.012 %) in the control group (MWU = 0.574), and 0.19 % (0.08-0.32 %) in the pregnant patients. All patients with FD/MAS and RANKL expression had thoracic bone lesions, but no correlation was observed between RANKL expression and presence of the GNAS mutation or FD disease burden. CONCLUSIONS: The triad of a higher number of patients, higher positive area percentage and stronger intensity in the FD/MAS compared to the control group indicates that RANKL may be upregulated in mammary tissue in a subset of patients with FD/MAS, which may explain the increased risk for breast cancer, although the clinical significance remains unclear. Further research is needed to establish risk profiles for the development of RANKL-positive breast cancer and to improve early screening and treatment.
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- 2023
4. The intricate mechanism of PLS3 in bone homeostasis and disease
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Zhong, W., Pathak, Janak L., Liang, Yueting, Zhytnik, L., Pals, G., Eekhoff, E.M.W., Bravenboer, N., and Micha, D.
- Published
- 2023
5. Mechanosensitivity of osteocytes in their native matrix
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Zhang, Chen, Klein Nulend, Jenneke, Bravenboer, N, Oral Cell Biology, Klein-Nulend, Jenneke, Bravenboer, Nathalie, Laboratory Specialized Diagnostics & Reseach, AMS - Tissue Function & Regeneration, and AMS - Ageing & Vitality
- Abstract
Osteocytes sense and transduce mechanical signals into biochemical signals, thereby regulating the adaptation of bone to mechanical loading. Their deep location in hard mineralized bone matrix hinders their isolation from bone, and thereby limits studies on osteocytes in vitro. In chapter 2, we reviewed two-dimensional (2D) and three-dimensional (3D) in vitro models of osteocytes with a special focus on models used to determine the mechanosensity and mechanoresponsiveness of osteocytes. We concluded that osteocytes are mostly studied in 2D-monolayer culture, but that 3D in vitro models of osteocyte-like cells and primary osteocytes have been established as well. 3D-osteocyte models mimic the native environment of osteocytes and show superior osteocyte morphology and behavior, enabling the development of human disease models. Osteocytes cultured in their native matrix resemble osteocytes in their in vivo situation most closely. The native matrix of osteocytes affects their mechanoresponsiveness. To study the role of the matrix surrounding the osteocytes in their mechanoresponsiveness, we developed, in chapter 3, a 3D-mechanical loading model of human cortical bone containing osteocytes in their native matrix. Using our model, mechanical loading can be reliably applied to osteocytes in their native matrix. Mechanically loaded osteocytes in their native matrix maintained their viability, and slightly upregulated SOST expression with increasing mechanical loading magnitude up to 8000 µɛ. This demonstrated that osteocytes in our model showed responsiveness to mechanical loading, indicating that our model is suitable for further studies on the role of healthy or diseased native matrix on osteocyte mechanoresponsiveness. Moreover, osteocytes in their native matrix responded to 1,25-dihydroxyvitamin D3, which indicates that our model can be used for studies on the role of small molecules in bone metabolism, and for drug screening. The mechanism of osteocyte-regulated mechanical adaptation of bone is not fully understood. More insight into target gene expression in osteocytes in their native matrix in response to mechanical loading is necessary. In chapter 4, we identified mechanosensitive genes by mapping the response of osteocytes in their native matrix to mechanical loading using RNA sequencing. Forty-seven new differentially expressed genes by mechanical loading were discovered in osteocytes in their native bone matrix. Eleven of these genes were related to bone metabolism. The functional aspects of these genes will be further explored, since they might play a role in the mechanical adaptation of bone. Our findings will be helpful to unravel the possible role of osteocytes in metabolic bone diseases, thereby providing new insight in the pathogenesis of these diseases, and facilitating potential gene targeted therapy. The inherited bone disorder osteogenesis imperfecta (OI) is characterized by bone fragility. Most OI patients have mutations leading to defected type I collagen, which is the main protein component of the extracellular matrix of bone. Osteocytes play an important role in bone homeostasis, but whether and how the function of osteocytes is affected in OI is unknown. In chapter 5, we studied whether abnormalities in OI bone matrix affect the osteocyte response to mechanical loading. Isolated non-OI and OI osteocytes cultured in monolayer showed similar mechanoresponsiveness, indicating that after removal of the altered bone matrix, isolated OI osteocytes retained their normal ability to respond to mechanical loading. This demonstrates that intrinsic mechanosensing by osteocytes is unaffected in OI. Moreover, osteocytes in OI bone matrix exhibited an altered response to mechanical loading compared to osteocytes in non-OI bone matrix. Abnormalities in OI bone matrix, i.e. hypermineralized collagenous matrix, may affect osteocyte mechanoresponsiveness, which could be partly responsible for the bone fragility in OI patients. This study provided new insight in the pathogenesis of OI, which may contribute to the development of new strategies for OI treatment in the future.
- Published
- 2023
6. Natural Polymers and Osteogenic Cells for Bone Tissue Regeneration
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Cao, Wei, Klein-Nulend, Jenneke, Schulten, Engelbert, Wu, Gang, Bravenboer, Nathalie, Amsterdam Movement Sciences, Amsterdam Movement Sciences - Restoration and Development, Oral and Maxillofacial Surgery / Oral Pathology, Klein Nulend, Jenneke, Wu, G, Bravenboer, N, and Oral Cell Biology
- Abstract
Bone defects caused by systemic or local factors cannot heal spontaneously. The repair of critical-sized bone defects in clinical practice remains challenging due to limited clinically available bone-defect filling material. To stimulate bone regeneration and resolve this clinical challenge, bone tissue engineering approaches have been developed during the past decades. Osteocytes have multiple functions in bone tissue. They can sense fluid shear stress as a result of mechanical loading, translating the mechanical stress into the production of biochemical signaling molecules. These effective biomolecules further regulate bone resorption and bone formation. Thus, it may well be that osteocytes not only regulate bone turnover but are also able to enhance osteogenesis of stem cells, suggesting a novel yet unrecognized role of osteocytes in governing bone tissue regeneration. In Chapter 2, we reviewed osteocyte functions in bone, as well as the interaction of osteocytes with other bone cells, and their role in bone remodeling. We hypothesize that osteocytes may have a pivotal role in bone regeneration as well, and thus that bone regeneration may be enhanced effectively and rapidly by optimal usage and stimulation of osteocytes. Currently available synthetic bone grafts are biocompatible and osteoconductive, but the majority of these biomaterials lack osteoinductivity. Biomaterials coated with various growth factors, proteins, and/or drugs promote the expansion and osteogenic differentiation of precursor cells. However, these growth factors or drugs might cause local and systemic adverse effects that hinder the clinical application for bone regeneration. Therefore, the search for safe and effective biomaterials to promote bone regeneration is still ongoing. In Chapter 3, we concluded that our results indicate a possible role of k-carrageenan in pre-osteoblast adhesion, spreading, migration, metabolic activity, proliferation, and osteogenic differentiation. This study fully explored the influence of k-carrageenan on cell function from different aspects that are needed for bone regeneration. The current results suggest that k-carrageenan might be a promising factor to functionalize bone graft and for enhanced osseointegration of implants. The search for cost-effective bioactive agents that can be incorporated in biomimetic calcium phosphate coating on an implant surface to improve implant osseointegration is still ongoing. k-Carrageenan could be a potent factor to improve implant osteoinductivity and osseointegration when incorporated in a calcium phosphate coating on titanium implants. In Chapter 4, we successfully incorporated k-carrageenan in an octa-calcium phosphate (OCP) coating on a titanium surface using a biomimetic co-precipitation technique. We found that k-carrageenan in the OCP coating increased pre-osteoblast spreading, proliferation, and metabolic activity, as well as alkaline phosphatase (ALP) activity, matrix mineralization, and osteogenic gene expression suggesting that k-carrageenan-functionalized OCP coating might improve osseointegration of titanium dental or orthopedic implants. Confined cell-cell and/or cell-scaffold interactions in three-dimensional (3D)-printed scaffolds containing β-tricalcium phosphate (TCP) limit bone regeneration and large bone defect repair. Stem cell culture systems have attracted considerable attention as a way to better mimic the complex interactions between individual cells and scaffolds that occur in vivo. Spheroids might be a promising strategy to improve cell-cell and/or cell-scaffold interactions to achieve ideal bone regeneration. In Chapter 5, we successfully developed self-assembled stem cells from human exfoliated deciduous teeth (SHEDs) µ-spheroids that enhanced the osteogenic potential of 3D-printed hydroxypropyl methylcellulose/polyethylenimine/β-TCP composite scaffolds in vitro and in vivo, suggesting that SHEDs µ-spheroids may be promising in bone tissue engineering for bone regeneration. Collectively, natural polymers and osteogenic cells do affect bone tissue regeneration. Bone regeneration modulated by osteocytes, k-carrageenan, and SHEDs µ-spheroids is promising in bone tissue engineering. Investigation of these processes provides further opportunities to learn and elucidate the mechanisms involved, leading to the development of new strategies for bone regeneration.
- Published
- 2023
7. Bone marrow adipose tissue and bone metabolism
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Beekman, Kerensa Mattanja, den Heijer, M., Maas, M., Bravenboer, N., Bisschop, P.H.L.T., den Heijer, Martin, Maas, Mario, Bravenboer, Nathalie, Bisschop, Peter, Radiology and nuclear medicine, Internal medicine, and APH - Health Behaviors & Chronic Diseases
- Abstract
In this thesis we explored the association between bone marrow adipose tissue (BMAT) and bone metabolism, to ultimately determine if BMAT might be a potential new imaging biomarker or potential new treatment target for osteoporosis. As patients with osteoporosis have low bone mineral density (BMD) combined with high BMAT, and bone marrow adipocytes (BMAds) and osteoblasts share a common progenitor, it is hypothesized that preferential differentiation towards adipocytes causes increased bone marrow adiposity and decreased bone formation. A second hypothesis is that BMAds have paracrine effects on bone metabolism. BMAT is a dynamic tissue. Neonates have little BMAT and during our life BMAT increases from the extremities in a centripetal way. In chapter 2 we show the specific pattern of BMAT distribution within the spine, pelvis, femur and tibia in a group of healthy subjects. BMAT increased from cranial to caudal within the spine, from proximal to distal within femora and showed a small, but consistent decrease from proximal to distal within tibiae. Furthermore, we show that the age-related increase in BMAT is gender and location dependent. As BMAT fatty acid unsaturation is associated with fractures, we also quantified BMAT fatty acid unsaturation. The association between BMAT and BMAT fatty acid unsaturation was opposed, depending on the location. Within the spine, BMAT and unsaturation were negatively correlated, while in the femora and tibiae BMAT and unsaturation were positively correlated. The gender specific differences in BMAT patterns observed in chapter 2 could possibly be mediated by sex steroids as estrogen treatment decreases BMAT and increases BMD. In chapter 3 we found no effect of raloxifene (a selective estrogen receptor modulator, registered for treatment of osteoporosis) on BMAT, adipocyte size or number, quantified in bone biopsies of postmenopausal women with osteoporosis. We found that BMAT volume and bone marrow adipocyte size both were negatively associated with osteoclast number, suggesting an association between BMAT and bone resorption. Furthermore, we found that women with osteoporosis and vertebral fractures had higher BMAT compared to women with osteoporosis without vertebral fractures, while there was no difference in bone volume between these groups, which could possibly indicate that BMAT is associated with fracture risk independent of bone volume. The negative association between BMAT and bone resorption could potentially be mediated by receptor activator of nuclear factor κ-B ligand (RANKL). Bone resorption is regulated by RANKL, which is expressed by osteocytes, osteoblasts and bone marrow precursor cells. In chapter 4 we showed that mature bone marrow adipocytes also express RANKL in a mouse model of postmenopausal osteoporosis (ovariectomy). Furthermore, we showed that estrogen deficiency caused by ovariectomy, not only increased BMAT, but also increased the percentage of RANKL positive BMAds. In chapter 5, we sought to inhibit adipogenesis by administration of a PPARγ antagonist, in the same mouse model of postmenopausal osteoporosis, to determine if we could prevent bone loss caused by estrogen deficiency. However, in these animals, administration of the PPARγ antagonist had no effect on BMAT, bone turnover, bone volume nor on bone strength. Postmenopausal estrogen deficiency is associated with increased visceral adipose tissue (VAT), and increased VAT is associated with increased BMAT and decreased BMD, suggesting an association between body composition and BMAT. Furthermore, patients with anorexia nervosa have high BMAT and low BMD. In chapter 6 we explore the effect of weight loss by gastric bypass surgery on BMAT and BMD in morbidly obese postmenopausal women. We found that both BMAT and BMD decreases after weight loss due to gastric bypass surgery, suggesting that BMAT does not contribute to bone loss after gastric bypass in postmenopausal women.
- Published
- 2021
8. Functional Insights in PLS3-Mediated Osteogenic Regulation.
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Zhong W, Neugebauer J, Pathak JL, Li X, Pals G, Zillikens MC, Eekhoff EMW, Bravenboer N, Zhang Q, Hammerschmidt M, Wirth B, and Micha D
- Subjects
- Animals, Humans, Mice, Fibroblasts metabolism, Osteoblasts metabolism, Zebrafish Proteins metabolism, Zebrafish Proteins genetics, Gene Knockdown Techniques, Zebrafish metabolism, Zebrafish genetics, Osteogenesis genetics, Microfilament Proteins metabolism, Microfilament Proteins genetics, Membrane Glycoproteins metabolism, Membrane Glycoproteins genetics, Cell Differentiation
- Abstract
Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients' fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1 , Nos1ap , and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism.
- Published
- 2024
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9. In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells.
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Claeys L, Zhytnik L, Ventura L, Wisse LE, Eekhoff EMW, Pals G, Bravenboer N, Heine VM, and Micha D
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- Humans, Cell Differentiation, Collagen metabolism, Skin, Osteogenesis genetics, Osteogenesis Imperfecta genetics, Osteogenesis Imperfecta metabolism, Mesenchymal Stem Cells metabolism, Induced Pluripotent Stem Cells
- Abstract
(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2 , NANOG , and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR , TFAP2A , and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73 , CD105 , and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.
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- 2024
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10. Microstructural changes in the irradiated and osteoradionecrotic bone: a SEM study.
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Sridhar Reddy P, Villikka K, Kashyap B, Dekker H, Schulten EAJM, Mikkonen JJW, Turunen M, Koistinen AP, Bravenboer N, and Kullaa AM
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- Humans, Microscopy, Electron, Scanning, Osteocytes pathology, Haversian System, Mandible pathology, Osteoradionecrosis etiology, Osteoradionecrosis pathology
- Abstract
Radiation exposure is a major health concern due to bone involvement including mandible, causing deleterious effects on bone metabolism, and healing with an increasing risk of infection and osteoradionecrosis. This study aims to investigate the radiotherapy-induced microstructural changes in the human mandible by scanning electron microscopy (SEM). Mandibular cortical bone biopsies were obtained from control, irradiated, and patients with osteoradionecrosis (ORN). Bone samples were prepared for light microscopy and SEM. The SEM images were analyzed for the number of osteons, number of Haversian canal (HC), diameter of osteon (D.O), the diameter of HC (D.HC), osteonal wall thickness (O.W.Th), number of osteocytes, and number of osteocytic dendrites. The number of osteons, D.O, D.HC, O.W.Th, the number of osteocytes, and osteocytic dendrites were significantly decreased in both irradiated and ORN compared to controls ( p < .05). The number of HCs decreased in irradiated and ORN bone compared to the control group. However, this was statistically not significant. The deleterious effect of radiation continues gradually altering the bone quality, structure, cellularity, and vascularity in the long term (>5 years mean radiation biopsy interval). The underlying microscopic damage in bone increases its susceptibility and contributes further to radiation-induced bone changes or even ORN.
- Published
- 2024
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11. Long-Term Safety of Bone Regeneration Using Autologous Stromal Vascular Fraction and Calcium Phosphate Ceramics: A 10-Year Prospective Cohort Study.
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Wu V, Klein-Nulend J, Bravenboer N, Ten Bruggenkate CM, Helder MN, and Schulten EAJM
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- Humans, Bone Regeneration, Calcium Phosphates adverse effects, Ceramics, Prospective Studies, Stromal Vascular Fraction, Clinical Trials, Phase I as Topic, Follow-Up Studies, Bone Substitutes adverse effects, Dental Implants, Sinus Floor Augmentation methods
- Abstract
This prospective cohort study aimed to assess long-term safety, dental implant survival, and clinical and radiological outcomes after maxillary sinus floor elevation (MSFE; lateral window technique) using freshly isolated autologous stromal vascular fraction (SVF) combined with calcium phosphate ceramics. All 10 patients previously participating in a phase I trial were included in a 10-year follow-up. They received either β-tricalcium phosphate (β-TCP; n = 5) or biphasic calcium phosphate (BCP; n = 5) with SVF-supplementation on one side (study). Bilaterally treated patients (6 of 10; 3 β-TCP, 3 BCP) received only calcium phosphate on the opposite side (control). Clinical and radiological assessments were performed on 44 dental implants at 1-month pre-MSFE, and 0.5- to 10-year post-MSFE. Implants were placed 6 months post-MSFE. No adverse events or pathology was reported during a 10-year follow-up. Forty-three dental implants (98%) remained functional. Control and study sides showed similar peri-implant soft-tissue quality, sulcus bleeding index, probing depth, plaque index, keratinized mucosa width, as well as marginal bone loss (0-6 mm), graft height loss (0-6 mm), and graft volume reduction. Peri-implantitis was observed around 6 implants (control: 4; study: 2) in 3 patients. This study is the first to demonstrate the 10-year safety of SVF-supplementation in MSFE for jawbone reconstruction. SVF-supplementation showed enhanced bone regeneration in the short term (previous study) and led to no abnormalities clinically and radiologically in the long term., (© The Author(s) 2023. Published by Oxford University Press.)
- Published
- 2023
- Full Text
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12. The intricate mechanism of PLS3 in bone homeostasis and disease.
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Zhong W, Pathak JL, Liang Y, Zhytnik L, Pals G, Eekhoff EMW, Bravenboer N, and Micha D
- Subjects
- Humans, Mutation, Bone and Bones pathology, Homeostasis, Mechanotransduction, Cellular, Osteoporosis pathology
- Abstract
Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it is puzzling how PLS3 specifically leads to bone-related disease presentation. Our review aims to summarize the current state of knowledge regarding the function of PLS3 in the predominant cell types in the bone tissue, the osteocytes, osteoblasts and osteoclasts. This is related to the role of PLS3 in regulating mechanotransduction, calcium regulation, vesicle trafficking, cell differentiation and mineralization as part of the complex bone pathology presented by PLS3 defects. Considering the consequences of PLS3 defects on multiple aspects of bone tissue metabolism, our review motivates the study of its mechanism in bone diseases which can potentially help in the design of suitable therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhong, Pathak, Liang, Zhytnik, Pals, Eekhoff, Bravenboer and Micha.)
- Published
- 2023
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13. Methodological aspects of in vivo axial loading in rodents: a systematic review.
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Nepal AK, van Essen HW, de Jongh RT, van Schoor NM, Otten RHJ, Vanderschueren D, Lips P, and Bravenboer N
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- Female, Rats, Mice, Animals, Bone and Bones, Bone Density, Weight-Bearing, Stress, Mechanical, Rodentia, Tibia
- Abstract
Axial loading in rodents provides a controlled setting for mechanical loading, because load and subsequent strain, frequency, number of cycles and rest insertion between cycles, are precisely defined. These methodological aspects as well as factors, such as ovariectomy, aging, and disuse may affect the outcome of the loading test, including bone mass, structure, and bone mineral density. This review aims to overview methodological aspects and modifying factors in axial loading on bone outcomes. A systematic literature search was performed in bibliographic databases until December 2021, which resulted in 2183 articles. A total of 144 articles were selected for this review: 23 rat studies, 74 mouse studies, and 47 knock out (KO) mouse studies. Results indicated that peak load, frequency, and number of loading cycles mainly affected the outcomes of bone mass, structure, and density in both rat and mouse studies. It is crucial to consider methodological parameters and modifying factors such as age, sex-steroid deficiency, and disuse in loading protocols for the prediction of loading-related bone outcomes., Competing Interests: The authors have no conflict of interest.
- Published
- 2023
14. Editorial: Rare musculoskeletal disorders: disease mechanisms and therapies.
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Seefried L, Bravenboer N, and Imel EA
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- Humans, Osteogenesis Imperfecta, Musculoskeletal Diseases therapy
- Abstract
Competing Interests: LS received honoraria for lectures and advice from AstraZeneca/Alexion, Amgen, Chiesi, Gedeon-Richter, GlaxoSmithKline, Inozyme, Ipsen, KyowaKirin, medi, STADA, Theramex and UCB and support for scientific projects to the institution from AstraZeneca/Alexion, Chiesi, KyowaKirin and Novartis. EAI received research funding from Ultragenyx, Kyowa Kirin, Amgen, Sanofi, Calciolytix, and has received honoraria for advising or consulting fees from Kyowa Kirin, Ultragenyx, Inozyme, and Agios. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
- Full Text
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15. The Effect of Sclerostin and Monoclonal Sclerostin Antibody Romosozumab on Osteogenesis and Osteoclastogenesis Mediated by Periodontal Ligament Fibroblasts.
- Author
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Pigeaud KE, Rietveld ML, Witvliet AF, Hogervorst JMA, Zhang C, Forouzanfar T, Bravenboer N, Schoenmaker T, and de Vries TJ
- Subjects
- Humans, Cells, Cultured, Fibroblasts, Periodontal Ligament, Leukocytes, Mononuclear, Osteogenesis
- Abstract
Sclerostin is a bone formation inhibitor produced by osteocytes. Although sclerostin is mainly expressed in osteocytes, it was also reported in periodontal ligament (PDL) fibroblasts, which are cells that play a role in both osteogenesis and osteoclastogenesis. Here, we assess the role of sclerostin and its clinically used inhibitor, romosozumab, in both processes. For osteogenesis assays, human PDL fibroblasts were cultured under control or mineralizing conditions with increasing concentrations of sclerostin or romosozumab. For analyzing osteogenic capacity and alkaline phosphatase (ALP) activity, alizarin red staining for mineral deposition and qPCR of osteogenic markers were performed. Osteoclast formation was investigated in the presence of sclerostin or romosozumab and, in PDLs, in the presence of fibroblasts co-cultured with peripheral blood mononuclear cells (PBMCs). PDL-PBMC co-cultures stimulated with sclerostin did not affect osteoclast formation. In contrast, the addition of romosozumab slightly reduced the osteoclast formation in PDL-PBMC co-cultures at high concentrations. Neither sclerostin nor romosozumab affected the osteogenic capacity of PDL fibroblasts. qPCR analysis showed that the mineralization medium upregulated the relative expression of osteogenic markers, but this expression was barely affected when romosozumab was added to the cultures. In order to account for the limited effects of sclerostin or romosozumab, we finally compared the expression of SOST and its receptors LRP-4, -5, and -6 to the expression in osteocyte rich-bone. The expression of SOST, LRP-4, and LRP-5 was higher in osteocytes compared to in PDL cells. The limited interaction of sclerostin or romosozumab with PDL fibroblasts may relate to the primary biological function of the periodontal ligament: to primarily resist bone formation and bone degradation to the benefit of an intact ligament that is indented by every chew movement.
- Published
- 2023
- Full Text
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16. Exploration of the skeletal phenotype of the Col1a1 +/Mov13 mouse model for haploinsufficient osteogenesis imperfecta type 1.
- Author
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Claeys L, Zhytnik L, Wisse LE, van Essen HW, Eekhoff EMW, Pals G, Bravenboer N, and Micha D
- Subjects
- Male, Mice, Animals, Female, X-Ray Microtomography, Mice, Inbred C57BL, Collagen genetics, Phenotype, Osteogenesis Imperfecta genetics, Osteogenesis Imperfecta pathology
- Abstract
Introduction: Osteogenesis Imperfecta is a rare genetic connective tissue disorder, characterized by skeletal dysplasia and fragile bones. Currently only two mouse models have been reported for haploinsufficient (HI) mild Osteogenesis Imperfecta (OI); the Col1a1
+/Mov13 (Mov13) and the Col1a1+/-365 mouse model. The Mov13 mice were created by random insertion of the Mouse Moloney leukemia virus in the first intron of the Col1a1 gene, preventing the initiation of transcription. Since the development of the Mov13 mice almost four decades ago and its basic phenotypic characterization in the 90s, there have not been many further studies. We aimed to extensively characterize the Mov13 mouse model in order to critically evaluate its possible use for preclinical studies of HI OI., Methods: Bone tissue from ten heterozygous Mov13 and ten wild-type littermates (WT) C57BL/6J mice (50% males per group) was analyzed at eight weeks of age with bone histomorphometry, micro computed tomography (microCT), 3-point bending, gene expression of different collagens, as well as serum markers of bone turnover., Results: The Mov13 mouse presented a lower bone strength and impaired material properties based on our results of 3-point bending and microCT analysis respectively. In contrast, no significant differences were found for all histomorphometric parameters. In addition, no significant differences in Col1a1 bone expression were present, but there was a significant lower P1NP concentration, a bone formation marker, measured in serum. Furthermore, bone tissue of Mov13 mice presented significantly higher expression of collagens ( Col1a2 , Col5a1 and Col5a2 ), and bone metabolism markers ( Bglap , Fgf23 , Smad7 , Edn1 and Eln ) compared to WT. Finally, we measured a significantly lower Col1a1 expression in heart and skin tissue and also determined a higher expression of other collagens in the heart tissue., Conclusion: Although we did not detect a significant reduction in Col1a1 expression in the bone tissue, a change in bone structure and reduction in bone strength was noted. Regrettably, the variability of the bone phenotype and the appearance of severe lymphoma in adult Mov13 mice, does not favor their use for the testing of new long-term drug studies. As such, a new HI OI type 1 mouse model is urgently needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Claeys, Zhytnik, Wisse, van Essen, Eekhoff, Pals, Bravenboer and Micha.)- Published
- 2023
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17. Mechanical loading modulates phosphate related genes in rat bone.
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Nepal AK, van Essen HW, Reijnders CMA, Lips P, and Bravenboer N
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- Animals, Female, Rats, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Bone Density, Calcification, Physiologic, Phosphates
- Abstract
Mechanical loading determines bone mass and bone structure, which involves many biochemical signal molecules. Of these molecules, Mepe and Fgf23 are involved in bone mineralization and phosphate homeostasis. Thus, we aimed to explore whether mechanical loading of bone affects factors of phosphate homeostasis. We studied the effect of mechanical loading of bone on the expression of Fgf23, Mepe, Dmp1, Phex, Cyp27b1, and Vdr. Twelve-week old female rats received a 4-point bending load on the right tibia, whereas control rats were not loaded. RT-qPCR was performed on tibia mRNA at 4, 5, 6, 7 or 8 hours after mechanical loading for detection of Mepe, Dmp1, Fgf23, Phex, Cyp27b1, and Vdr. Immunohistochemistry was performed to visualise FGF23 protein in tibiae. Serum FGF23, phosphate and calcium levels were measured in all rats. Four-point bending resulted in a reduction of tibia Fgf23 gene expression by 64% (p = 0.002) and a reduction of serum FGF23 by 30% (p<0.001), six hours after loading. Eight hours after loading, Dmp1 and Mepe gene expression increased by 151% (p = 0.007) and 100% (p = 0.007). Mechanical loading did not change Phex, Cyp27b1, and Vdr gene expression at any time-point. We conclude that mechanical loading appears to provoke both a paracrine as well as an endocrine response in bone by modulating factors that regulate bone mineralization and phosphate homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nepal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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18. Mapping the Response of Human Osteocytes in Native Matrix to Mechanical Loading Using RNA Sequencing.
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Zhang C, van Essen HW, Sie D, Micha D, Pals G, Klein-Nulend J, and Bravenboer N
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Osteocytes sense mechanical loads and transduce mechanical signals into a chemical response. They are the most abundant bone cells deeply embedded in mineralized bone matrix, which affects their regulatory activity in the mechanical adaptation of bone. The specific location in the calcified bone matrix hinders studies on osteocytes in the in vivo setting. Recently, we developed a three-dimensional mechanical loading model of human osteocytes in their native matrix, allowing to study osteocyte mechanoresponsive target gene expression in vitro. Here we aimed to identify differentially expressed genes by mapping the response of human primary osteocytes in their native matrix to mechanical loading using RNA sequencing. Human fibular bone was retrieved from 10 donors (age: 32-82 years, 5 female, 5 male). Cortical bone explants (8.0 × 3.0 × 1.5 mm; length × width × height) were either not loaded or mechanically loaded by 2000 or 8000 μɛ for 5 minutes, followed by 0, 6, or 24 hours post-culture without loading. High-quality RNA was isolated, and differential gene expression analysis performed by R2 platform. Real-time PCR was used to confirm differentially expressed genes. Twenty-eight genes were differentially expressed between unloaded and loaded (2000 or 8000 μɛ) bone at 6 hours post-culture, and 19 genes at 24 hours post-culture. Eleven of these genes were related to bone metabolism, ie, EGR1 , FAF1 , H3F3B , PAN2 , RNF213 , SAMD4A , and TBC1D24 at 6 hours post-culture, and EGFEM1P , HOXD4 , SNORD91B , and SNX9 at 24 hours post-culture. Mechanical loading significantly decreased RNF213 gene expression, which was confirmed by real-time PCR. In conclusion, mechanically loaded osteocytes differentially expressed 47 genes, of which 11 genes were related to bone metabolism. RNF213 might play a role in mechanical adaptation of bone by regulating angiogenesis, which is a prerequisite for successful bone formation. The functional aspects of the differentially expressed genes in bone mechanical adaptation requires future investigation. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)
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- 2023
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19. Bone vitality and vascularization of mandibular and maxillary bone grafts in maxillary sinus floor elevation: A retrospective cohort study.
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Wu V, Schulten EAJM, Helder MN, Ten Bruggenkate CM, Bravenboer N, and Klein-Nulend J
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- Humans, Maxilla surgery, Maxilla pathology, Maxillary Sinus surgery, Retrospective Studies, Bone Transplantation, Dental Implantation, Endosseous, Sinus Floor Augmentation, Dental Implants
- Abstract
Objectives: Mandibular retromolar (predominantly cortical) and maxillary tuberosity (predominantly cancellous) bone grafts are used in patients undergoing maxillary sinus floor elevation (MSFE) for dental implant placement. The aim of this retrospective cohort study was to investigate whether differences exist in bone formation and vascularization after grafting with either bone source in patients undergoing MSFE., Methods: Fifteen patients undergoing MSFE were treated with retromolar (n = 9) or tuberosity (n = 6) bone grafts. Biopsies were taken 4 months postoperatively prior to dental implant placement, and histomorphometrically analyzed to quantify bone and osteoid area, number of total, apoptotic, and receptor activator of nuclear factor-κB ligand (RANKL)-positive osteocytes, small and large-sized blood vessels, and osteoclasts. The grafted area was divided in three regions (caudal-cranial): RI, RII, and RIII., Results: Bone volume was 40% (RII, RIII) higher and osteoid volume 10% (RII) lower in retromolar compared to tuberosity-grafted areas. Total osteocyte number and number of RANKL-positive osteocytes were 23% (RII) and 90% (RI, RII) lower, but osteoclast number was higher (retromolar: 12, tuberosity: 0) in retromolar-grafted areas. The total number of blood vessels was 80% (RI) to 60% (RIII) lower, while the percentage of large-sized blood vessels was 86% (RI) to 25% (RIII) higher in retromolar-grafted areas. Number of osteocyte lacunae and apoptotic osteocytes were similar in both bone grafts used., Conclusions: Compared to the retromolar bone, tuberosity bone showed increased bone vitality and vascularization in patients undergoing MSFE, likely due to faster bone remodeling or earlier start of new bone formation. Therefore, tuberosity bone grafts might perform better in enhancing bone regeneration., (© 2022 The Authors. Clinical Implant Dentistry and Related Research published by Wiley Periodicals LLC.)
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- 2023
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20. Molecular Quantity Variations in Human-Mandibular-Bone Osteoid.
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Palander A, Fauch L, Turunen MJ, Dekker H, Schulten EAJM, Koistinen A, Bravenboer N, and Kullaa A
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- Humans, Bone Matrix, Osteoblasts, Collagen, Calcification, Physiologic, Bone and Bones, Bone Diseases
- Abstract
Osteoid is a layer of new-formed bone that is deposited on the bone border during the process of new bone formation. This deposition process is crucial for bone tissue, and flaws in it can lead to bone diseases. Certain bone diseases, i.e. medication related osteonecrosis, are overexpressed in mandibular bone. Because mandibular bone presents different properties than other bone types, the data concerning osteoid formation in other bones are inapplicable for human-mandibular bone. Previously, the molecular distribution of other bone types has been presented using Fourier-transform infrared (FTIR) spectroscopy. However, the spatial distribution of molecular components of healthy-human-mandibular-bone osteoid in relation to histologic landmarks has not been previously presented and needs to be studied in order to understand diseases that occur human-mandibular bone. This study presents for the first time the variation in molecular distribution inside healthy-human-mandibular-bone osteoid by juxtaposing FTIR data with its corresponding histologic image obtained by autofluorescence imaging of its same bone section. During new bone formation, bone-forming cells produce an osteoid constituted primarily of type I collagen. It was observed that in mandibular bone, the collagen type I increases from the osteoblast line with the distance from the osteoblasts, indicating progressive accumulation of collagen during osteoid formation. Only later inside the collagen matrix, the osteoid starts to mineralize. When the mineralization starts, the collagen accumulation diminishes whereas the collagen maturation still continues. This chemical-apposition process in healthy mandibular bone will be used in future as a reference to understand different pathologic conditions that occur in human-mandibular bone., (© 2022. The Author(s).)
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- 2022
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21. Kappa-carrageenan-Functionalization of octacalcium phosphate-coated titanium Discs enhances pre-osteoblast behavior and osteogenic differentiation.
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Cao W, Jin J, Wu G, Bravenboer N, Helder MN, Schulten EAJM, Bacabac RG, Pathak JL, and Klein-Nulend J
- Abstract
Bioactive coatings are promising for improving osseointegration and the long-term success of titanium dental or orthopaedic implants. Biomimetic octacalcium phosphate (OCP) coating can be used as a carrier for osteoinductive agents. κ-Carrageenan, a highly hydrophilic and biocompatible seaweed-derived sulfated-polysaccharide, promotes pre-osteoblast activity required for bone regeneration. Whether κ-carrageenan can functionalize OCP-coating to enhance osseointegration of titanium implants is unclear. This study aimed to analyze carrageenan-functionalized biomimetic OCP-coated titanium structure, and effects of carrageenan functionalization on pre-osteoblast behavior and osteogenic differentiation. Titanium discs were coated with OCP/κ-carrageenan at 0.125-2 mg/ml OCP solution, and physicochemical and biological properties were investigated. κ-Carrageenan (2 mg/ml) in the OCP coating of titanium discs decreased the pore size in the sheet-like OCP crystal by 41.32%. None of the κ-carrageenan concentrations tested in the OCP-coating did affect hydrophilicity. However, κ-carrageenan (2 mg/ml) increased (1.26-fold) MC3T3-E1 pre-osteoblast spreading at 1 h i.e., κ-Carrageenan in the OCP-coating increased pre-osteoblast proliferation (max. 1.92-fold at 2 mg/ml, day 1), metabolic activity (max. 1.50-fold at 2 mg/ml, day 3), and alkaline phosphatase protein (max. 4.21-fold at 2 mg/ml, day 3), as well as matrix mineralization (max. 5.45-fold at 2 mg/ml, day 21). κ-Carrageenan (2 mg/ml) in the OCP-coating increased gene expression of Mepe (4.93-fold) at day 14, and Runx2 (2.94-fold), Opn (3.59-fold), Fgf2 (3.47-fold), Ocn (3.88-fold), and Dmp1 (4.59-fold) at day 21 in pre-osteoblasts. In conclusion, κ-carrageenan modified the morphology and microstructure of OCP-coating on titanium discs, and enhanced pre-osteoblast metabolic activity, proliferation, and osteogenic differentiation. This suggests that κ-carrageenan-functionalized OCP coating may be promising for in vivo improvement of titanium implant osseointegration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Jin, Wu, Bravenboer, Helder, Schulten, Bacabac, Pathak and Klein-Nulend.)
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- 2022
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22. Irradiation Induced Biochemical Changes in Human Mandibular Bone: A Raman Spectroscopic Study.
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Reddy Padala S, Saikia D, Mikkonen JJW, Uurasjärvi E, Dekker H, Schulten EAJM, Bravenboer N, Koistinen A, Chauhan A, Singh SP, and Kullaa AM
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- Carbonates, Durapatite chemistry, Humans, Principal Component Analysis, Mandible radiation effects, Spectrum Analysis, Raman methods
- Abstract
Understanding the biochemical changes in irradiated human mandible after radiotherapy of cancer patients is critical for oral rehabilitation. The underlying mechanism for radiation-associated changes in the bone at the molecular level could lead to implant failure and osteoradionecrosis. The study aimed to assess the chemical composition and bone quality in irradiated human mandibular bone using Raman spectroscopy. A total of 33 bone biopsies from 16 control and 17 irradiated patients were included to quantify different biochemical parameters from the Raman spectra. The differences in bone mineral and matrix band intensities between control and irradiated groups were analyzed using unpaired Student's t -test with statistical significance at p < 0.05. Findings suggest that the intensity of the phosphate band is significantly decreased and the carbonate band is significantly increased in the irradiated group. Further, the mineral crystallinity and carbonate to phosphate ratio are increased. The mineral to matrix ratio is decreased in the irradiated group. Principal component analysis (PCA) based on the local radiation dose and biopsy time interval of irradiated samples did not show any specific classification between irradiation sub-groups. Irradiation disrupted the interaction and bonding between the organic matrix and hydroxyapatite minerals affecting the bone biochemical properties. However, the normal clinical appearance of irradiated bone would have been accompanied by underlying biochemical and microscopical changes which might result in radiation-induced delayed complications.
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- 2022
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23. Osteogenic transdifferentiation of primary human fibroblasts to osteoblast-like cells with human platelet lysate.
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Cayami FK, Claeys L, de Ruiter R, Smilde BJ, Wisse L, Bogunovic N, Riesebos E, Eken L, Kooi I, Sistermans EA, Bravenboer N, Pals G, Faradz SMH, Sie D, Eekhoff EMW, and Micha D
- Subjects
- Calcification, Physiologic genetics, Cell Differentiation genetics, Fibroblasts, Humans, Osteogenesis genetics, Cell Transdifferentiation genetics, Osteoblasts metabolism
- Abstract
Inherited bone disorders account for about 10% of documented Mendelian disorders and are associated with high financial burden. Their study requires osteoblasts which play a critical role in regulating the development and maintenance of bone tissue. However, bone tissue is not always available from patients. We developed a highly efficient platelet lysate-based approach to directly transdifferentiate skin-derived human fibroblasts to osteoblast-like cells. We extensively characterized our in vitro model by examining the expression of osteoblast-specific markers during the transdifferentiation process both at the mRNA and protein level. The transdifferentiated osteoblast-like cells showed significantly increased expression of a panel of osteogenic markers. Mineral deposition and ALP activity were also shown, confirming their osteogenic properties. RNA-seq analysis allowed the global study of changes in the transcriptome of the transdifferentiated cells. The transdifferentiated cells clustered separately from the primary fibroblasts with regard to the significantly upregulated genes indicating a distinct transcriptome profile; transdifferentiated osteoblasts also showed significant enrichment in gene expression related to skeletal development and bone mineralization. Our presented in vitro model may potentially contribute to the prospect of studying osteoblast-dependent disorders in patient-derived cells., (© 2022. The Author(s).)
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- 2022
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24. Gender- and Age-Associated Differences in Bone Marrow Adipose Tissue and Bone Marrow Fat Unsaturation Throughout the Skeleton, Quantified Using Chemical Shift Encoding-Based Water-Fat MRI.
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Beekman KM, Regenboog M, Nederveen AJ, Bravenboer N, den Heijer M, Bisschop PH, Hollak CE, Akkerman EM, and Maas M
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- Adipose Tissue diagnostic imaging, Animals, Bone and Bones diagnostic imaging, Cross-Sectional Studies, Female, Humans, Lumbar Vertebrae diagnostic imaging, Magnetic Resonance Imaging methods, Male, Bone Marrow diagnostic imaging, Water
- Abstract
Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22-75 years; 14 female: mean age 50 years, range 29-71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water-fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( ± SD or (IQR): cervical spine 0.37 ± 0.1; thoracic spine 0.41 ± 0.08. lumbar spine 0.46 ± 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 ± 0.09; diaphysis 0.86 (0.15); distal 0.93 ± 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 ± 0.01; diaphysis 0.91 (0.02); distal 0.90 ± 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (ρ = 0.88 p < 0.001; ρ = 0.87 p < 0.001; ρ = 0.63 p = 0.02; ρ = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (ρ = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beekman, Regenboog, Nederveen, Bravenboer, den Heijer, Bisschop, Hollak, Akkerman and Maas.)
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- 2022
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25. Osteocyte Apoptosis, Bone Marrow Adiposity, and Fibrosis in the Irradiated Human Mandible.
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Dekker H, Schulten EAJM, Lichters I, van Ruijven L, van Essen HW, Blom GJ, Bloemena E, Ten Bruggenkate CM, Kullaa AM, and Bravenboer N
- Abstract
Purpose: To assess the effect of radiation therapy on osteocyte apoptosis, osteocyte death, and bone marrow adipocytes in the human mandible and its contribution to the pathophysiology of radiation damage to the mandibular bone., Methods and Materials: Mandibular cancellous bone biopsies were taken from irradiated patients and nonirradiated controls. Immunohistochemical detection of cleaved caspase-3 was performed to visualize apoptotic osteocytes. The number of apoptotic osteocytes per bone area and per total amount of osteocytes, osteocytes per bone area, and empty lacunae per bone area were counted manually. The percentage fibrotic tissue and adipose tissue per bone marrow area, the percentage bone marrow of total area, and the mean adipocyte diameter (μm) was determined digitally from adjacent Goldner stained sections., Results: Biopsies of 15 irradiated patients (12 men and 3 women) and 7 nonirradiated controls (5 men and 2 women) were assessed. In the study group a significant increase was seen in the number of empty lacunae, the percentage of adipose tissue of bone marrow area, and the adipocyte diameter. There was no significant difference in bone marrow fibrosis nor apoptotic osteocytes between the irradiated group and the controls., Conclusions: Irradiation alone does not seem to induce excessive bone marrow fibrosis. The damage to bone mesenchymal stem cells leads to increased marrow adipogenesis and decreased osteoblastogenic potential. Early osteocyte death resulting in avital persisting bone matrix with severely impaired regenerative potential may contribute to the vulnerability of irradiated bone to infection and necrosis., (© 2022 The Author(s).)
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- 2022
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26. A Three-Dimensional Mechanical Loading Model of Human Osteocytes in Their Native Matrix.
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Zhang C, Farré-Guasch E, Jin J, van Essen HW, Klein-Nulend J, and Bravenboer N
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- Bone Matrix, Bone and Bones, Humans, Osteoblasts, Stress, Mechanical, Osteoclasts, Osteocytes metabolism
- Abstract
Osteocytes are mechanosensory cells which are embedded in calcified collagenous matrix. The specific native matrix of osteocytes affects their regulatory activity, i.e., transmission of signaling molecules to osteoclasts and/or osteoblasts, in the mechanical adaptation of bone. Unfortunately, no existing in vitro model of cortical bone is currently available to study the mechanosensory function of human osteocytes in their native matrix. Therefore, we aimed to develop an in vitro three-dimensional mechanical loading model of human osteocytes in their native matrix. Human cortical bone explants containing osteocytes in their three-dimensional native matrix were cultured and mechanically loaded by three-point bending using a custom-made loading apparatus generating sinusoidal displacement. Osteocyte viability and sclerostin expression were measured 1-2 days before 5 min loading and 1 day after loading. Bone microdamage was visualized and quantified by micro-CT analysis and histology using BaSO
4 staining. A linear relationship was found between loading magnitude (2302-13,811 µɛ) and force (1.6-4.9 N) exerted on the bone explants. At 24 h post-loading, osteocyte viability was not affected by 1600 µɛ loading. Sclerostin expression and bone microdamage were unaffected by loading up to 8000 µɛ. In conclusion, we developed an in vitro 3D mechanical loading model to study mechanoresponsiveness of viable osteocytes residing in their native matrix. This model is suitable to study the effect of changed bone matrix composition in metabolic bone disease on osteocyte mechanoresponsiveness., (© 2021. The Author(s).)- Published
- 2022
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27. Contemporary kidney transplantation has a limited impact on bone microarchitecture.
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Meng C, Jørgensen HS, Verlinden L, Bravenboer N, de Loor H, D'Haese PC, Carmeliet G, and Evenepoel P
- Abstract
Bone microarchitecture is an important component of bone quality and disturbances may reduce bone strength and resistance to trauma. Kidney transplant recipients have an excess risk of fractures, and bone loss affecting both trabecular and cortical bone compartments have been demonstrated after kidney transplantation. The primary aim of this study was to investigate the impact of kidney transplantation on trabecular and cortical bone microarchitecture, assessed by histomorphometry and micro computed tomography (μCT). Iliac crest bone biopsies, analyzed by bone histomorphometry and μCT, were performed at time of kidney transplantation and 12 months post-transplantation in an unselected cohort of 30 patients. Biochemical markers of mineral metabolism and bone turnover were measured at both time-points. At 12 months post-transplantation, bone turnover was low in 5 (17%) and normal in 25 (83%) patients. By histomorphometry, bone remodeling normalized, with decreases in eroded perimeters (4.0 to 2.1%, p = 0.02) and number of patients with marrow fibrosis (41 to 0%, p < 0.001). By μCT, trabecular thickness (134 to 125 μM, p = 0.003) decreased slightly. Other parameters of bone volume and microarchitecture, including cortical thickness (729 to 713 μm, p = 0.73) and porosity (10.2 to 9.5%, p = 0.15), remained stable. We conclude that kidney transplantation with current immunosuppressive protocols has a limited impact on bone microarchitecture., Competing Interests: PE reports personal fees from Amgen and Vifor-FMC. Remaining authors have no conflicts of interest to declare., (© 2022 The Authors. Published by Elsevier Inc.)
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- 2022
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28. Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review.
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Treurniet S, Burger P, Ghyczy EAE, Verbraak FD, Curro-Tafili KR, Micha D, Bravenboer N, Ralston SH, de Vries R, Moll AC, and Eekhoff EMW
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- Blindness physiopathology, Eye Diseases diagnosis, Humans, Osteogenesis Imperfecta genetics, Phenotype, Risk Factors, Blindness etiology, Collagen Type I genetics, Eye Diseases complications, Mutation, Osteogenesis Imperfecta complications
- Abstract
Purpose: Osteogenesis imperfecta (OI) is a rare inherited heterogeneous connective tissue disorder characterized by bone fragility, low bone mineral density, skeletal deformity and blue sclera. The dominantly inherited forms of OI are predominantly caused by mutations in either the COL1A1 or COL1A2 gene. Collagen type I is one of the major structural proteins of the eyes and therefore is the eye theoretically prone to alterations in OI. The aim of this systematic review was to provide an overview of the known ocular problems reported in OI., Methods: A literature search (in PubMed, Embase and Scopus), which included articles from inception to August 2020, was performed in accordance with the PRISMA guidelines., Results: The results of this current review show that almost every component of the eye could be affected in OI. Decreased thickness of the cornea and sclera is an important factor causing eye problems in patients with OI such as blue sclera. Findings that stand out are ruptures, lacerations and other eye problems that occur after minor trauma, as well as complications from standard surgical procedures., Discussion: Alterations in collagen type I affect multiple structural components of the eye. It is recommended that OI patients wear protective glasses against accidental eye trauma. Furthermore, when surgery is required, it should be approached with caution. The prevalence of eye problems in different types of OI is still unknown. Additional research is required to obtain a better understanding of the ocular defects that may occur in OI patients and the underlying pathology., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)
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- 2022
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29. Irradiation affects the structural, cellular and molecular components of jawbones.
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Padala SR, Kashyap B, Dekker H, Mikkonen JJW, Palander A, Bravenboer N, and Kullaa AM
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- Animals, Bone and Bones, Osteogenesis, Reactive Oxygen Species metabolism, Bone Resorption, Radiation, Ionizing
- Abstract
Purpose: Emerging evidence shows that changes in the bone and its microenvironment following radiotherapy are associated with either an inhibition or a state of low bone formation. Ionizing radiation is damaging to the jawbone as it increases the complication rate due to the development of hypovascular, hypocellular, and hypoxic tissue. This review summarizes and correlates the current knowledge on the effects of irradiation on the bone with an emphasis on jawbone, as these have been a less extensively studied area., Conclusions: The stringent regulation of bone formation and bone resorption can be influenced by radiation, causing detrimental effects at structural, cellular, vascular, and molecular levels. It is also associated with a high risk of damage to surrounding healthy tissues and an increased risk of fracture. Technological advances and research on animal models as well as a few human bone tissue studies have provided novel insights into the ways in which bone can be affected by high, low and sublethal dose of radiation. The influence of radiation on bone metabolism, cellular properties, vascularity, collagen, and other factors like inflammation, reactive oxygen species are discussed.
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- 2022
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30. Regional differences in microarchitecture and mineralization of the atrophic edentulous mandible: A microcomputed tomography study.
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Dekker H, Schulten EAJM, Ten Bruggenkate CM, Bloemena E, van Ruijven LJ, and Bravenboer N
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- Bicuspid diagnostic imaging, Female, Humans, Male, Molar diagnostic imaging, X-Ray Microtomography, Bone Density, Mandible diagnostic imaging
- Abstract
Objective: The aim of the present study was to assess mineralization and trabecular microarchitecture in atrophic edentulous mandibles and to identify regional differences and relations with the extent of resorption., Methods: Cortical and trabecular bone volumes in anterior, premolar and molar regions of 10 edentulous cadaveric mandibles (5 males and 5 females; mean age ± SD: 85.4 ± 8.3 years) were assessed by microcomputed tomography. Mandibular height and Cawood & Howell classes were recorded. Concerning trabecular volumes, bone mineral density (BMD), bone volume fraction, trabecular tissue volume fraction, connectivity density, trabecular number, trabecular thickness, trabecular separation, degree of anisotropy, and structural model index were measured; concerning cortical volumes porosity, BMD and cortical thickness were measured., Results: In molar regions, the bone volume fraction and trabecular number were lower, whereas trabecular separation, degree of anisotropy and cortical BMD were higher compared to anterior regions. In premolar regions, mandibular height correlated negatively with trabecular number (Spearman's correlation r = 0.73, p = 0.017) and connectivity density (Spearman's correlation r = 0.82, p = 0.004), and correlated positively with trabecular separation (Spearman's correlation r = - 0.65, p = 0.04). Cortical BMD was higher at bucco-inferior cortex of molar and inferior border of premolar region and lower at anterior cranial buccal and lingual surface., Conclusions: In the premolar region, increased resorption coincides with local impairment of trabecular bone quality. Cortical bone BMD is higher in areas with highest strains and lower in areas with most mandibular resorption. Trabecular bone volume and quality is superior in the anterior region of the edentulous mandible, which might explain improved primary stability of dental implants in this region., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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31. Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.
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de Ruiter RD, Smilde BJ, Pals G, Bravenboer N, Knaus P, Schoenmaker T, Botman E, Sánchez-Duffhues G, Pacifici M, Pignolo RJ, Shore EM, van Egmond M, Van Oosterwyck H, Kaplan FS, Hsiao EC, Yu PB, Bocciardi R, De Cunto CL, Longo Ribeiro Delai P, de Vries TJ, Hilderbrandt S, Jaspers RT, Keen R, Koolwijk P, Morhart R, Netelenbos JC, Rustemeyer T, Scott C, Stockklausner C, Ten Dijke P, Triffit J, Ventura F, Ravazzolo R, Micha D, and Eekhoff EMW
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- Congresses as Topic, Endocrinology methods, Expert Testimony trends, History, 21st Century, Humans, Mutation physiology, Ossification, Heterotopic genetics, Ossification, Heterotopic pathology, Endocrinology trends, Myositis Ossificans diagnosis, Myositis Ossificans etiology, Myositis Ossificans pathology, Myositis Ossificans therapy
- Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Ruiter, Smilde, Pals, Bravenboer, Knaus, Schoenmaker, Botman, Sánchez-Duffhues, Pacifici, Pignolo, Shore, van Egmond, Van Oosterwyck, Kaplan, Hsiao, Yu, Bocciardi, De Cunto, Longo Ribeiro Delai, de Vries, Hilderbrandt, Jaspers, Keen, Koolwijk, Morhart, Netelenbos, Rustemeyer, Scott, Stockklausner, ten Dijke, Triffit, Ventura, Ravazzolo, Micha and Eekhoff.)
- Published
- 2021
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32. K-Carrageenan Stimulates Pre-Osteoblast Proliferation and Osteogenic Differentiation: A Potential Factor for the Promotion of Bone Regeneration?
- Author
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Cao W, Jin J, Wu G, Bravenboer N, Helder MN, Pathak JL, Zandieh-Doulabi B, Hogervorst JMA, Matsukawa S, Geonzon LC, Bacabac RG, Schulten EAJM, and Klein-Nulend J
- Subjects
- Animals, Bone Regeneration drug effects, Carrageenan metabolism, Cell Culture Techniques, Cell Differentiation drug effects, Cell Line, Cell Proliferation drug effects, Mice, Osteoblasts drug effects, Osteoblasts metabolism, Osteogenesis physiology, Tissue Engineering methods, Bone Regeneration physiology, Carrageenan pharmacology, Osteogenesis drug effects
- Abstract
Current cell-based bone tissue regeneration strategies cannot cover large bone defects. K-carrageenan is a highly hydrophilic and biocompatible seaweed-derived sulfated polysaccharide, that has been proposed as a promising candidate for tissue engineering applications. Whether κ-carrageenan can be used to enhance bone regeneration is still unclear. In this study, we aimed to investigate whether κ-carrageenan has osteogenic potential by testing its effect on pre-osteoblast proliferation and osteogenic differentiation in vitro. Treatment with κ-carrageenan (0.5 and 2 mg/mL) increased both MC3T3-E1 pre-osteoblast adhesion and spreading at 1 h. K-carrageenan (0.125-2 mg/mL) dose-dependently increased pre-osteoblast proliferation and metabolic activity, with a maximum effect at 2 mg/mL at day three. K-carrageenan (0.5 and 2 mg/mL) increased osteogenic differentiation, as shown by enhanced alkaline phosphatase activity (1.8-fold increase at 2 mg/mL) at day four, and matrix mineralization (6.2-fold increase at 2 mg/mL) at day 21. K-carrageenan enhanced osteogenic gene expression ( Opn , Dmp1 , and Mepe ) at day 14 and 21. In conclusion, κ-carrageenan promoted MC3T3-E1 pre-osteoblast adhesion and spreading, metabolic activity, proliferation, and osteogenic differentiation, suggesting that κ-carrageenan is a potential osteogenic inductive factor for clinical application to enhance bone regeneration.
- Published
- 2021
- Full Text
- View/download PDF
33. Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice.
- Author
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Schilperoort M, Kroon J, Kooijman S, Smit AE, Gentenaar M, Mletzko K, Schmidt FN, van Ruijven L, Busse B, Pereira AM, Appelman-Dijkstra NM, Bravenboer N, Rensen PCN, Meijer OC, and Winter EM
- Subjects
- Animals, Circadian Rhythm, Female, Mice, Osteoporosis physiopathology, Phenotype, Glucocorticoids adverse effects, Osteoporosis chemically induced
- Abstract
Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow-release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age-related risk of osteoporosis., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
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