Bone Remodeling Activity Research Articles

Effects of Biliopancreatic Diversion on Bone Turnover Markers and Association with Hormonal Factors in Patients with Severe Obesity.

This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3days, 3 and 12months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12months after BPD. Three participants were lost to follow-up. CTX increased significantly at 3days (+ 66%), 3months (+ 219%), and 12months (+ 295%). OC decreased at 3days (- 19%) then increased at 3months (+ 69%) and 12months (+ 164%). Change in sclerostin was only significant between 3days and 3months (+ 13%), while change in OPG was significant between baseline and 3days (+ 48%) and baseline and 12months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = - 0.63, p = 0.009) and 12months (r = - 0.58, p = 0.039), and total BMD decrease (r = - 0.67, p = 0.033) at 12months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.

The Influence of Leaping Frequency on Secondary Bone in Cercopithecid Primates

Bone remodeling is at least partially mediated by the mechanical environment created by an animal's behavior. Here, we test the hypothesis that bone remodeling is primarily induced by high magnitude loads, likely encountered during leaping/bounding behaviors. Osteon population density (OPD), osteon cross-sectional area (On.Ar), and relative osteonal area (%HAV) were measured from femoral and humeral midshaft thin sections of four cercopithecids (N = 5 per species) from Taï Forest, Côte d'Ivoire: Colobus polykomos, Piliocolobus badius, Cercopithecus diana, and Cercocebus atys. All species are generalized quadrupeds but vary in leaping frequency and overall activity budget. Differences between taxa with high (C. polykomos and P. badius) and low leaping frequency (C. diana and C. atys) were assessed via a phylogenetically informed generalized linear mixed model using Markov Chain Monte Carlo methods. Femoral OPD and %HAV are greater in the high frequency leapers than in low frequency leapers, suggesting that frequent high magnitude loads engender remodeling, however, there is no similar pattern in the humerus, which presumably also experiences high magnitude loads during leaping. Additionally, OPD and %HAV are greater in the humerus than the femur, despite load magnitude being presumably higher in the femur. These results provide conflicting support for hypotheses about load magnitude and load frequency as they relate to bone remodeling activity. Future work is proposed to parse out the respective effects of load magnitude and frequency on bone remodeling. Anat Rec, 302:1116-1126, 2019. © 2018 Wiley Periodicals, Inc.

Bone Regeneration of Canine Peri-implant Defects Using Cell Sheets of Adipose-Derived Mesenchymal Stem Cells and Platelet-Rich Fibrin Membranes

Insufficient bone volume compromises the success rate and osseointegration of immediate implantation. The objective of the present study was to engineer bone tissue by using adipose-derived stem cell (ASC) sheets and autologous platelet-rich fibrin (PRF) to enhance new bone formation and osseointegration around dental implants. The proliferation and osteogenic potential of ASCs treated with autologous PRF were evaluated with CCK-8 assays, alkaline phosphatase staining, and real-time quantitative polymerase chain reaction. A 3-wall bone defect around each immediate implant was generated in the mandible and randomly treated with ASC sheets plus PRF (group A), ASC sheets only (group B), PRF only (group C), or no treatment (group D). Micro-computed tomography, biomechanical tests, fluorescent bone labeling, and histologic assessments were performed to evaluate bone regeneration capacity. The proliferation and osteogenic potential of canine ASCs were markedly enhanced by PRF. Group A exhibited considerably more new bone formation and re-osseointegration (41.17±1.44 and 55.06±0.06%, respectively) than did the other 3 groups. Fluorescent labeling showed that the most rapid bone remodeling activity occurred in group A (P<.05). These results suggest that sheets of ASC combined with autologous PRF could be a promising tissue-engineering strategy for bone formation in immediate implantation.

Natural history of mineral metabolism, bone turnover and bone mineral density in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol.

The skeletal effects of renal transplantation are not completely understood, especially in patients managed with a steroid minimization immunosuppressive protocol and long term. We enrolled 69 adult transplant recipients (39 males; ages 51.1 ± 12.2 years), free of antiresorptive therapy and managed with a steroid minimization immunosuppressive protocol, into a 5-year prospective observational study to evaluate changes in areal bone mineral density (aBMD), mineral metabolism and bone remodelling. Dual energy X-ray absorptiometry, laboratory parameters of mineral metabolism (including parathyroid hormone, sclerostin and fibroblast growth factor 23) and non-renal cleared bone turnover markers (BTMs) (bone-specific alkaline phosphatase, trimeric N-terminal propeptide and tartrate-resistant acid phosphatase 5b) were assessed at baseline and 1 and 5 years post-transplantation. The mean cumulative methylprednisolone exposure at 1 and 5 years amounted to 2.5 ± 0.8 and 5.8 ± 3.3 g, respectively. Overall, bone remodelling activity decreased after transplantation. Post-transplant aBMD changes were minimal and were significant only in the ultradistal radius during the first post-operative year {median -2.2% [interquartile range (IQR) -5.9-1.2] decline, P = 0.01} and in the lumbar spine between Years 1 and 5 [median 1.6% (IQR -3.2-7.0) increase, P = 0.009]. BTMs, as opposed to mineral metabolism parameters and cumulative corticosteroid exposure, associated with aBMD changes, both in the early and late post-transplant period. Most notably, aBMD changes inversely associated with bone remodelling changes. In summary, in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol, BMD changes are limited, highly variable and related to remodelling activity rather than corticosteroid exposure.

Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches

The bone is essential for locomotion, calcium storage, and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of Pparγ (peroxisome proliferator-activated receptor-γ), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia-initiating cells and increased survival upon transplantation. Taken together, our data identify PTIP as an epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.

Nitrogen-containing bisphosphonate therapy-Part II: Assessment of alveolar bone tissue inflammatory response in rats-A blind randomized controlled trial.

This study aimed to evaluate the alveolar bone tissue inflammatory response in rats undergoing zoledronic acid therapy. The study sample was composed of 28 Wistar rats. Animals from the test group GTa received a weekly intraperitoneal dose of 0.2mg/kg of zoledronic acid for 3weeks, while test group GTb received the same dose for 8weeks. A physiological saline dose, equivalent to that of the medication, was administered to the controls in groups GCa and GCb. A defect was created in the dental crown of the lower first molars using a drill to simulate pulp and periapical injury. Data were evaluated regarding image grey levels by cone-beam computed tomography and histologically by assigning scores for the presence of inflammatory infiltrate, type of infiltrate, vascularization, bone necrosis and dental resorption. Grey levels in the 3-week therapy group (GTa) showed more pronounced changes in comparison with those seen in the GCa group (P<0.05). Evaluation of the scores demonstrated no association between any of the variables amongst the groups (>0.05). However, bone remodelling decreased in the groups receiving themedication. Bone necrosis was present more frequently in group GTb than in the control group GCb. The results suggest that the drug interfered in the reaction capacity of the alveolar bone tissue as test group GTa showed higher grey levels in comparison to the control group GCa. In addition, there was less bone remodelling activity, with the appearance of bone necrosis zones and intense acute inflammatory infiltrate associated with the 8-week therapy group GTb.

Implants in patients with antiresorptive therapy ‐ Dos and Don’ts

Antiresorptive agents, e.g. bisphosphonates or denosumab reduce bone remodeling activity and may be responsible for necrosis also in patients with osteoporosis. In implantology in particular, the relationship between implant survival and bisphosphonate intake has been investigated almost exclusively in recent years. A specific question in the context of the anamnesis and targeted risk evaluation is urgently needed here. In this context, the DGI checklist gives a practical advice.

The Effects of Vitamin E from Elaeis guineensis (Oil Palm) in a Rat Model of Bone Loss Due to Metabolic Syndrome.

The beneficial effects of vitamin E in improving components of MetS or bone loss have been established. This study aimed to investigate the potential of palm vitamin E (PVE) as a single agent, targeting MetS and bone loss concurrently, using a MetS animal model. Twelve-week-old male Wistar rats were divided into five groups. The baseline group was sacrificed upon arrival. The normal group was given standard rat chow. The remaining three groups were fed with high-carbohydrate high-fat (HCHF) diet and treated with tocopherol-stripped corn oil (vehicle), 60 mg/kg or 100 mg/kg PVE. At the end of the study, the rats were evaluated for MetS parameters and bone density. After euthanasia, blood and femurs were harvested for the evaluation of lipid profile, bone histomorphometric analysis, and remodeling markers. PVE improved blood pressure, glycemic status, and lipid profile; increased osteoblast surface, osteoid surface, bone volume, and trabecular thickness, as well as decreased eroded surface and single-labeled surface. Administration of PVE also significantly reduced leptin level in the HCHF rats. PVE is a potential agent in concurrently preventing MetS and protecting bone loss. This may be, in part, achieved by reducing the leptin level and modulating the bone remodeling activity in male rats.

Abstract A048: Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases

Abstract Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histologic evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2), and osteocytes (SOST), we found high osteoblast activity to be coupled to high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2-positive osteoblasts and TRAP (ACP5)-positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment-naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity in metastasis tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and to patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histologic evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserves further exploration. Citation Format: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström. Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A048.

Vγ9Vδ2 T cells inhibit immature dendritic cell transdifferentiation into osteoclasts through downregulation of RANK, c‑Fos and ATP6V0D2.

Osteoimmunological studies have revealed that T cells exert a powerful impact on the formation and activity of osteoclasts and bone remodeling. Evidence demonstrates that immature dendritic cells (iDCs) are more efficient transdifferentiating into osteoclasts (OCs) than monocytes. However, whether Vγ9Vδ2 T (γδ T) cells stimulate or inhibit iDC transdifferentiation into OCs has never been reported. The aim of the present study was to investigate the effects of γδ T cells on this transdifferentiation process. γδ T cells and iDCs were isolated from the peripheral blood of healthy volunteers separately and were co-cultured with Transwelll inserts, with γδ T cells in the upper chamber and iDCs in the lower chamber. IDCs were treated with macrophage-colony stimulating factor and receptor activator of nuclear factor-κB (RANK) ligand. Tartrate resistant acid phosphatase (TRAP) assay and dentine resorption assay were performed to detect OC formation and their resorption capacity, respectively. The mRNA expression of OCs was examined using a micro-array and real time-quantitative polymerase chain reaction to trace the changes during iDC transdifferentiation into OCs. The results demonstrated that γδ T cells significantly inhibited the generation of the TRAP-positive OCs from iDCs and their resorption capacity. The microarray analysis identified decreased expression level of Fos proto-oncogene AP-1 transcription factor subunit (c-Fos), ATPase H+ transporting V0 subunit d (ATP6V0D2) and cathepsin K when iDCs were co-cultured with γδ T cells. These genes are associated with OC differentiation, indicating that γδ T cells suppressed iDCs osteoclastogenesis by downregulation of the RANK/c-Fos/ATP6V0D2 signaling pathway. The present findings provide novel insights into the interactions between human γδ T cells and iDCs, and demonstrate that γδ T cells are capable of inhibiting OC formation and their activity via downregulation of genes associated with OC differentiation.

Novel nano-hydroxyapatite/polyurethane composite scaffold in the treatment of chronic osteomyelitis

To evaluate the bone repair efficacy of the new nano-hydroxyapatite (n-HA)/polyurethane (PU) composite scaffold in the treatment of chronic osteomyelitis in tibia. A novel levofloxacin@mesoporous silica microspheres (Lev@MSNs)/n-HA/PU was successfully synthesized. Its surface structure was observed by scanning electron microscopy (SEM). Fifty adult female New Zealand rabbits were randomly selected, and osteomyelitis was induced in the right tibia of the rabbit by injecting bacterial suspension ( Staphylococcus aureus; 3×10 7 CFU/mL), which of the method was described by Norden. A total of 45 animals with the evidence of osteomyelitis were randomly divided into 4 groups, and the right medullary cavity of each animal was exposed. Animals in the blank control group (group A, n=9) were treated with exhaustive debridement only. The remaining animals were first treated by exhaustive debridement, and received implantations of 5 mg Lev@PMMA (group B, n=12), 1 mg Lev@MSNs/n-HA/PU (group C, n=12), and 5 mg Lev@MSNs/n-HA/PU (group D, n=12), respectively. At 12 weeks postoperatively, the right tibia of rabbits were observed by X-ray film, and then gross observation, methylene blue/acid fuchsin staining, and SEM observation of implant-bone interface, as well as biomechanical test (measuring the maximal compression force) were performed. X-ray films showed that the infection were severer than those of preoperation in group A, while the control of inflammation and bone healing of rabbits in group D were obviously better than those at preoperation. The gross observation showed extensive bone destruction in group A, a significant gap between bone tissue and the material in groups B and C, and close combination between bone tissue and the material in group D. The histology of the resected specimens showed that there was no obvious new bone formation around the materials in groups B and C, and there was abundant new bone formation around the periphery and along the voids of the materials and active bone remodeling in group D. The SEM observation of the bone-implant interface demonstrated that no new bone formation was observed at the bone-implant interface in groups B and C. However, bony connections and blurred boundaries were observed between the material and host bone tissue in group D. The biomechanical test showed the maximal compression force of groups B and D were significantly higher than that of groups A and C ( P<0.05), but there was no significant difference between groups B and D ( P>0.05). The novel synthetic composite Lev@MSNs/n-HA/PU exhibit good antibacterial activities, osteoconductivity, and biomechanical properties, and show great potential in the treatment of chronic osteomyelitis of rabbits.

Abstract 3671: Phenotypic heterogeneity within prostate cancer bone metastases measured by 18F-DCFBC PET/CT and 18F-NaF PET/CT

Abstract Purpose: The purpose of this study was to compare the spatial colocalization of prostate-specific membrane antigen (PSMA) targeting agent 18F-DCFBC PET/CT, a marker which demonstrates correlation with tumor aggressiveness, and 18F-NaF PET/CT, a marker of osteoblastic activity, within bone lesions of patients with metastatic prostate cancer. Methods: Twenty-eight metastatic prostate cancer patients received 18F-DCFBC PET/CT and 18F-NaF PET/CT scans (median interval 7 days, range 1-57). Tracer-specific regions of interest (ROI) were derived from threshold containing 80% of maximum SUV (SUV80%). Lesion detection and uptake was compared across the two PET/CT agents using non-parametric testing (Spearman correlation, Wilcoxon rank sum) accounting for intra-patient correlation. Lesion-specific registration was completed by global alignment of skeletal segments followed by local neighborhood optimization of area surrounding lesion. Spatial concordance was evaluated using overlap volume (OV), calculated as the volume of ROI intersection (shared volume) relative to the minimum volume of NaF-ROI or PSMA-ROI to account for differences in ROI volumes. Differences in uptake and CT Hounsfield units (HU) were compared within concordant (overlapping) and discordant (NaF-only, PSMA-only) regions of the same lesion using Wilcoxon signed rank test accounting for intra-patient correlation. Results: Twenty-six patients had positive NaF or DCFBC PET/CT scans, with a total of 241 metastatic sites identified. Lesion-level NaF SUV80% and DCFBC-2hr SUV80% were not significantly correlated at baseline (ρ=0.41, p&amp;gt;0.1). Lesion-level NaF-SUV80% was lower in bone lesions detected only by NaF (N=96) compared to NaF-SUV80% in bone lesions detected by both tracers (N=82), nearing significance (p=0.065). This pattern was not observed in DCFBC-SUV80% (p=0.5). To avoid bias from motion artifacts, only lesions in pelvis and spine were considered for voxel-based analysis (N=42). NaF and PSMA ROIs showing varying levels of spatial concordance (OV mean=0.26, range=0-1), which was modestly associated with higher sclerosis (ρ=0.4, p=0.01) and weakly associated with lower PSMA activity (ρ=0.3, p=0.07). Intra-lesion PSMA-only regions were significantly less sclerotic compared to concordant (p=0.04) and NaF-only (p=0.03) regions, indicating regions of active tumor seeding extend beyond regions of active bone remodeling within the tumor. Conclusions: Metastatic seeding and growth of prostate cancer in bone is biologically complex and dependent on bone microenvironment. We find regions of aggressive cellular activity (PSMA-targeting PET/CT) show heterogeneous colocalization with regions of rapid bone remodeling (NaF PET/CT) within sites of metastatic bone disease. These preliminary findings are important for consideration of targeted radionuclide therapies in metastatic prostate cancer. Citation Format: Stephanie A. Harmon, Esther Mena, Joanna Shih, Ethan Bergvall, Stephen Adler, Sherif Mehralivand, Ravi A. Madan, James L. Gulley, William L. Dahut, Baris Turkbey, Peter L. Choyke, M Liza Lindenberg. Phenotypic heterogeneity within prostate cancer bone metastases measured by 18F-DCFBC PET/CT and 18F-NaF PET/CT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3671.

Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats

The decreased bone mass and impaired osteogenesis capacities that occur with aging may influence the outcome of dental implants. Parathyroid hormone (PTH) (1–34) is an anabolic agent for the treatment of osteoporosis. However, little is known about its effects and mechanisms on vascularized bone regeneration and implant osseointegration in aging. In current study, we adopted both in vivo and in vitro approaches to explore the mechanisms of early actions of PTH (1–34) on the angiogenic and osteogenic microenvironment to enhance implant osseointegration in aged rats. Daily subcutaneous injections of 30 μg/kg PTH (1–34) were given to female rats aged 20 months beginning on next day of implantation and lasting for 5 weeks. Radiological and histological analysis confirmed that PTH (1–34) improved new bone formation, angiogenesis and implant osseointegration in aged rats in the early stage. The osteogenic potential of aged bone mesenchymal stem cells (BMSCs) was enhanced, while their adipogenesis capacity was attenuated. Furthermore, PTH (1–34) was shown to promote angiogenesis directly via endothelial cell migration and blood vessel formation in vitro. Meanwhile, PTH (1–34) stimulated more osteoclasts participation in bone remodeling by secreting angiogenic and osteogenic growth factors to induce early vascularization and stimulate the migration or differentiation of BMSCs indirectly. Together, these results demonstrate mechanistic insight into how PTH (1–34) regulates the angiogenic and osteogenic microenvironment to result in more active bone remodeling and new bone formation, making it an excellent potential therapeutic agent for rapid vascularized bone regeneration and implant osseointegration in the aged population.

RUNX2 mutation reduces osteogenic differentiation of dental follicle cells in cleidocranial dysplasia.

Disturbed permanent tooth eruption is common in cleidocranial dysplasia (CCD), a skeletal disorder caused by heterozygous mutation of RUNX2, but the mechanism underlying is still unclear. As it is well known that dental follicle cells (DFCs) play a critical role in tooth eruption, the changed biological characteristics of DFCs might give rise to disturbance of permanent tooth eruption in CCD patients. Thus, primary DFCs from one CCD patient and normal controls were collected to investigate the effect of RUNX2 mutation on the bone remodeling activity of DFCs and explore the mechanism of impaired permanent tooth eruption in this disease. Conservation and secondary structure analysis revealed that the RUNX2 mutation (c.514delT, p.172fs) found in the present CCD patient was located in the highly conserved RUNT domain and converted the structure of RUNX2. After osteogenic induction, we found that the mineralised capacity of DFCs and the expression of osteoblast-related genes, including RUNX2, ALP, OSX, OCN and Col Iα1, in DFCs was severely interfered by the RUNX2 mutation found in CCD patients. To investigate whether the osteogenic deficiency of DFCs from the CCD patient can be rescued by RUNX2 restoration, we performed 'rescue' experiments. Surprisingly, the osteogenic deficiency and the abnormal expression of osteoblast-associated genes in DFCs from the CCD patient were almost rescued by overexpression of wild-type RUNX2 using lentivirus. All these findings indicate that RUNX2 mutation can reduce the osteogenic capacity of DFCs through inhibiting osteoblast-associated genes, thereby disturbing alveolar bone formation, which serves as a motive force for tooth eruption. This effect may provide valuable explanations and implications for the mechanism of delayed permanent tooth eruption in CCD patients.

Sinus Floor Elevation Using the Lateral Approach and Window Repositioning and a Xenogeneic Bone Substitute as a Grafting Material: A Histologic, Histomorphometric, and Radiographic Analysis.

Sinus floor elevation using the lateral approach and bone window repositioning and a xenogeneic bone substitute (Cerabone) has been well documented clinically. The purpose of this histologic and histomorphometric study was to determine the fate of the window, its contributing role in the healing process, and the osseoconductivity and resorption potential of the high-temperature sintered bovine bone used, as well as to correlate the histomorphometric results with sinus depth and lateral wall thickness as determined on cone beam computed tomography (CBCT). Thirty biopsy specimens were harvested from the lateral side of the maxilla of patients operated on for sinus floor elevation and implant placement at two postoperative periods: early, group 1 (mean: 5.73 ± 0.44 months); and late, group 2 (mean: 8.68 ± 1.76 months). Sinus depth and lateral wall thickness were determined on CBCT and correlated to graft maturation. The repositioned bone window was microscopically detectable in both study groups and looked well integrated. Bone was found growing out of the repositioned window toward the center of the graft, most often forming a trabecular network independently from the bone matrix, which is in favor of osteogenic potential of the window. Also, newly built bone was found directly attached to the surfaces of the window, indicating bone growth via osseoconduction. Repositioned window sides showed signs of low-grade inflammation. Active osteoclasts were only found to be associated with the newly built bone matrix, hinting at an active bone remodeling process. No signs of biodegradation or remodeling of the window were detected using the tartrate-resistant acid phosphatase (TRAP) technique. The histomorphometric analysis of the tissue distribution showed similar values of newly formed bone in group 1 (22.77% ± 5.89%) and in group 2 (26.15% ± 11.18%) and connective tissue values in both study groups (42.29% ± 8.98% for group 1 vs 46.03% ± 5.84% for group 2). No significant differences were found between group 1 (34.94% ± 7.10%) and group 2 (27.82% ± 11.97%) for xenogeneic bone substitute values. Statistically significant differences were only found between connective tissue values and newly built bone values (P < .01 and P < .001, respectively). Furthermore, a significant difference was found between connective tissue values and that of bone substitute up to 12 months (P < .01). No significant correlation was found between sinus depth and lateral window thickness and histomorphometric results. The re positioned window technique appears to be a good osteoconductive barrier for bone formation. Its osteogenic potential needs to be confirmed immunochemically. High-temperature sintered bovine bone proved to be an effective slowly resorbing osseoconductive material.

Cellular and Molecular Mediators of Bone Metastatic Lesions.

Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of bone cells. This interplay between tumor and bone cells alters the physiological bone remodeling, leading to the generation of a vicious cycle that promotes bone metastasis growth. To prevent the skeletal-related events (SRE) associated with bone metastasis, approaches to inhibit osteoclast bone resorption are reported. The bisphosphonates and Denosumab are currently used in the treatment of patients affected by bone lesions. They act to prevent or counteract the SRE, including pathologic fractures, spinal cord compression, and pain associated with bone metastasis. However, their primary effects on tumor cells still remain controversial. In this review, a description of the mechanisms leading to the onset of bone metastasis and clinical approaches to treat them are described.

NAMPT expression in osteoblasts controls osteoclast recruitment in alveolar bone remodeling.

In bone remodeling, osteoclasts are recruited via increased production of RANKL (receptor activator of nuclear factor-κB ligand) and migrate to the bone surface, aided by matrix metalloproteinases (MMPs). NAMPT (nicotinamide phosphoribosyl transferase), which catalyzes the rate-limiting step in the NAD+ salvage pathway, increases during in vitro osteogenic differentiation and inhibits RANKL-induced osteoclast differentiation. Alveolar bone loss, due to disturbance of the remodeling process, is a major feature of periodontitis. Thus, we investigated the role of NAMPT in a synchronized alveolar bone remodeling rat model. NAMPT expression increased in osteogenic cells during the remodeling activation phase, in parallel with RANKL and MMP-2 expression. Inhibition of NAMPT activity, by systemic delivery of its selective inhibitor FK866, decreased the recruitment of osteoclasts, but not their activity. In vitro, NAMPT mRNA, and protein expression also increased during osteoblast differentiation in primary calvarial osteoblast cultures. Recombinant NAMPT and NMN, its direct metabolite, dose-dependently increased bone marker expression, including that of sialoprotein (BSP) and osteocalcin (OC), whereas their expression was inhibited by FK866 treatment. Recombinant NAMPT did not regulate MMP-2, -9, MMP-13, or RANKL/OPG mRNA expression in osteoblasts. Our data suggest that de novo NAMPT synthesis in osteoblasts controls cell differentiation through osteoclast recruitment during the activation of bone remodeling.

Effects of Photobiomodulation on SOFAT, A T-cell-derived Cytokine, May Explain Accelerated Orthodontic Tooth Movement.

Orthodontic tooth movement is based on mechanical forces inducing bone remodeling, and several methods have been proposed to increase tooth movement, including photobiomodulation. This study evaluated, in an animal model, the effects of photobiomodulation on SOFAT-a secreted osteoclastogenic factor of activated T cells and RANK-L during tooth movement. The results showed that tooth displacement, RANK-L and SOFAT levels were significantly greater compared to Control group. SOFAT may play an important role in bone remodeling during orthodontic movement, possibly increasing the osteoclast cells at the compression area and bone remodeling activity.

The Role of Extracellular Vesicles in Bone Metastasis.

Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. Despite being the focus of intense investigation, the molecular and cellular mechanisms that regulate the metastasis of disseminated tumor cells still remain largely unknown. Bone metastases severely impact quality of life since they are associated with pain, fractures, and bone marrow aplasia. In this review, we will summarize the recent discoveries on the role of extracellular vesicles (EV) in the regulation of bone remodeling activity and bone metastasis occurrence. Indeed, it was shown that extracellular vesicles, including exosomes and microvesicles, released from tumor cells can modify the bone microenvironment, allowing the formation of osteolytic, osteosclerotic, and mixed mestastases. In turn, bone-derived EV can stimulate the proliferation of tumor cells. The inhibition of EV-mediated crosstalk between cancer and bone cells could represent a new therapeutic target for bone metastasis.

Shaping the craniofacial skeleton of Mexican cavefish (Astyanax mexicanus); Role of Osteoblast and Osteoclast

The vertebrate bony skeleton is remodelled continuously by bone deposition and reabsorption, which is essential for normal development, growth, repair and for the mineral homeostasis. Remodelling of the skeleton usually involves the removal of the bone by osteoclasts and the subsequent formation of new bone by osteoblasts. These remodelling mechanisms can be found in the teleost fish skeleton with special adaptation to the aquatic life. Most of the fish species have teeth in their craniofacial region and replace their dentitions though out the life which lead to continuous bone remodelling activity in the tooth‐bearing bones. The Mexican tetra (Astyanax mexicanus), is a small teleost fish that exists as two morphs; sighted and blind cave form. The degeneration of the eyes, result in the characteristics craniofacial phenotype in cavefish. However, little is known about the cellular mechanisms underlying the remodelling activity of the skeleton of this species. This study was designed to identify the cellular interactions during the development of craniofacial skeleton of Mexican cavefish. Histological and whole mount analysis was performed to compare the development of the skeleton in these two morphs. The cavefish showed delayed eruption of teeth in tooth‐bearing bones but has large jaw bones compared to the surface larval fish. Sites of bone resorption in the bony skeleton will be investigated by RNA in situ hybridization and ultrastructural analysis. Live bone staining techniques will be used to identify the pattern of bone deposition. This study will provide insights into the evolution of osteoblastic and osteoclastic cell activity and will highlight the use of this species as a model in mammalian skeletal disorders.Support or Funding InformationThis research was funded by the University of Manitoba.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.