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Item Bone Remodeling and Strain Variation Following Altered Mandibular Condyle Loading in Retired Breeder Rabbits(1993) Puntillo, Anthony M.; Garetto, Lawrence P.; Roberts, W. Eugene; Arbuckle, Gordon R.; Chen, Jie; Burr, David B.Several investigators have demonstrated modeling of the mandibular condyle foil following a change in load. A recent study evaluated the effect of age on the ability of the condyle to adapt to such a change. The present study explored the early changes in the mandibular condyles of retired breeder rabbits following an alteration in load, and attempted to quantify this load. Twelve female retired breeder New Zealand white rabbits were divided into four equal groups. Under general anesthesia strain gauges were placed on the lateral inferior body of the mandible bilaterally in two of the groups. Two days post-surgery acrylic splints were placed on the anterior teeth (resulting in a posterior open bite) of one the strain gauge groups and one group that did not receive strain gauges. The splints were maintained for 26 days. A control group received neither strain gauges nor splints. Intravital bone labels were administered to all groups to allow for histomorphometric analysis of condylar modeling and remodeling. In addition, principal strain measurements were recorded pre- and post-splint placement. The histomorphometric findings revealed a significant (p<.03) decrease in the subcondylar space of animals that received splints. Splinted animals also showed a significant increase in labeled surface area (p<.02) and in volume percent label (p<.05) of the trabeculae in the condylar neck region. In addition, surgical placement of the strain gauges significantly (p<.05) decreased the labeling of the periosteal surface in the neck region. The strain gauges proved functional in most rabbits for only a few days and registered large variations and no discernible differences in average maximum microstrain, and average change in microstrain. It was concluded from these results that an incisal prematurity (causing a posterior openbite), 26 days in duration, caused an increase functional load on the condyle. This load resulted in an increase in trabecular label and decrease in porosity of the subchondral plate. The decreased subcondylar space is possibly an indication of stiffening in this region. A stiffening of this nature has been suggested in previous studies to be a precursor to osteoarthritic degeneration.Item Cell Kinetics of Osteoblast Histogenesis in Evolving Rabbit Secondary Haversian Systems Using a Double Labeling Technique with [³H]-Thymidine and Bromodeoxyuridine(1995) Sim, Yeongsuk; Roberts, Eugene; Garetto, Lawrence P.; Katona, Thomas R.; McDonald, James L.; Seifert, Mark F.The mechanism for internal cortical bone remodeling is orchestrated by the evolving secondary Haversian systems (SHSs), which originate on the surfaces of Volkmann's canals. During this coupled process, a cortical tunnel advances by the cutting cone of osteoclasts and closes by the bone-forming trail of osteoblasts. This study investigated the hypothesis that osteoblast histogenesis, within evolving SHSs of larger animals, is a vascular-related process, i.e., less differentiated osteogenic cells reside in close proximity to the advancing central blood vessel (CBV) while differentiating osteoblast precursors migrate toward the bone surface and become osteoblasts. Using a double-labeling method with [3 H]-thymidine and bromodeoxyuridine (BrdU), this study examined cell kinetics in 120 SHSs per rabbit at 12 hour intervals up to 72 hours after labeling. A total of 7 rabbits were injected with alizarin complexone (-1 O days: 20 mg/kg/day), tetracycline (-3 days: 10 mg/kg/day), [3H]-thymidine (time zero: 0.25 μCi/gm), and BrdU (1 hour before sacrifice: 25 mg/kg). The femoral midshaft was used for undecalcified fluorescent microscopic analysis of new bone vs. old bone and two adjacent diaphyseal tissues were demineralized for nuclear volume morphometric analysis of cells via light microscopy. Evolving SHSs demonstrating intense remodeling activity were selected for detailed cell kinetic analysis. The results showed that BrdU labeled cells were consistently located at the leading edge of the CBV (within 160 μm of its tip) and that the [3H]thymidine labeled cells were progressively left behind the advancing CBV (160 μm from the tip of CBV by 72 hours). The labeling indices (sampled 1 hour after labeling) between BrdU (10.6 ± 0.3 %) and [3H]-thymidine (14.4 ± 1.3 %) were comparable. Lightly labeled A+A' cells (identified as osteoprogenitor cells) remained in close approximation to the surface of the CBV (within 25 μm) and C+D cells (preosteoblasts) were located closer to bone-forming surfaces (~50 μm away from the CBV). The number of osteoblasts were increased up to 60 hours and about 22.5 ± 6.6 % of them survived to become osteocytes. The B cell compartment, characteristic of osteogenic tissues with a dense connective tissue component such as the periodontal ligament (POL), was essentially absent in the SHSs in this study. Although the direction of evolving SHSs was highly variable (caudally directed: 53.4 ± 11.2 % and rostrally directed: 41.6 ± 8.1 %), the osteogenic process along the advancing CBV was remarkably consistent. These results support the hypothesis that osteoblast histogenesis, associated with cortical bone remodeling, is a vascular-oriented differentiation process closely related to the internal angiogenesis within the evolving SHS. The primary proliferating region supporting osteogenesis was consistently located at the advancing tip of the CBV, suggesting the presence of a self-renewing, perivascular proliferative pool of cells accompanying the advancing vessel. In addition, a secondary proliferating region of cells trails the advancing CBV, providing for lateral migration of preosteoblasts to bone surfaces where they complete their development into functional osteoblasts. This study provides further insight into the similarities and differences in osteoblast histogenesis within evolving SHSs from adult rabbits and the more extensively studied rat POL model.Item Dystrophic spinal deformities in a neurofibromatosis type 1 murine model(PLoS, 2015-03-18) Rhodes, Steven D.; Zhang, Wei; Yang, Dalong; Yang, Hao; Chen, Shi; Wu, Xiahoua; Yang, Xianlin; Mohammad, Khalid S.; Guise, Theresa A.; Bergner, Amanda L.; Stevenson, David A.; Yang, Feng-Chun; Department of Anatomy and Cell Biology, IU School of MedicineDespite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.Item Effect of Aging on Bone Remodeling in Canine Mandibular Condyle(1998) Fernández, Aurora Paula; Garetto, Lawrence P.; Chen, Jie; Crow, Heidi; Katona, Thomas R.; Shanks, JamesPrevious research indicates that overall, bone turnover decreases with age. The effects of aging on the remodeling of the mandibular condyle have not been studied. As part of the temporomandibular joint, the mandibular condyle (MC) is exposed to a unique pattern of loading. As such, data obtained from studies of other bones may not be applicable to accurately explain the behavior of trabecular bone of the mandibular condyle and its relationship to aging. Recent research has led to the finding that cortical bone turnover in the mandible is much higher than that seen in tibia, and that both sites decline with age. The purpose of this study was to histomorphometrically quantify the effects of aging on the bone remodeling of the canine MC, and to determine whether site-specific differences due to age occur in the dynamic and static parameters between MC and tibial condyle (TC). Fluorochrome labels were used to mark sites of bone formation in ten old and five young dogs. Specimens were obtained from one MC and one TC for each dog and were prepared for analysis of static and dynamic histomorphometric indices. Mineral apposition and bone formation were totally absent in the old group, as shown by the lack of fluorochrome labels. In the young group, they were significantly higher in the MC than in the TC (p < 0.01). Aging resulted in a significant increase of volume density of the subchondral bone (p < 0.05). Trabecular bone volume was not significantly affected by age in the samples studied. The results indicate that bone remodeling is markedly higher in MC than in the TC in young dogs. With aging, it declines to zero in both sites. Whether the loss of remodeling activity in these elderly animals indicates that they are fully adapted to their mechanical environment or that they have lost the intrinsic ability to remodel, remains to be determined.Item The Effect of Alendronate and Risedronate on Bone Remodeling in the Canine Maxilla(1999) Callegari, Brent Joseph; Garetto, Lawrence P.; Hartsfield, James K., Jr.; Katona, Thomas R.; Turner, Charles H.; Shanks, James C.Bisphosphonates, effective inhibitors of bone resorption, are used in the treatment of postmenopausal osteoporosis. At present, the effects of bisphosphonate therapy on the maxilla have not been quantitatively studied. As part of the masticatory system, dentate alveolar bone is exposed to a unique pattern of loading. As such, data obtained from bisphosphonate studies of other bones may not be applicable to the cortical bone of the dentate maxilla. The objective of this study is to histomorphometrically quantify the effects of alendronate and risedronate therapy on alveolar bone of the dog maxilla (MX) and to determine if this site is affected differently than the cortical bone in the rib (R) from these same animals. Twenty-two female dogs were divided into three treatment groups of 1 mg/kg/day alendronate, 0.5 mg/kg/day risedronate, and a saline vehicle control. Fluorochrome labels were used to mark sites of bone formation. Maxillary and rib specimens from each dog were prepared for analysis of static and dynamic histomorphometric parameters. MX cortical bone surrounding the third premolar was further analyzed by side (buccal vs. lingual) and region (coronal vs. apical). Mineralizing surface (MS/BS) and bone formation rate (BFR) in the coronal maxilla of the control group is significantly (p < 0.05) higher than that of the bisphosphonate groups. In bisphosphonate treated animals, MS/BS, BFR, and activation frequency (AcF) were significantly (p < 0.05) higher in the R than in the MX. In all treatment groups, very little osteoid was detected, and no significant difference in the mineral apposition rate (MAR) was noted. These results indicate that: (1) bisphosphonate dosages used in this study effectively inhibited remodeling within the dog maxilla; (2) alveolar bone remodeling was decreased more than remodeling in rib cortical bone; (3) within the dentate maxilla, alveolar bone remodeling was decreased more in the coronal than in the apical region, and (4) none of the groups appears to show inhibition of mineralization.Item Effect of Etidronate on Bone Remodeling in Dog Mandibular Condyle(1998) Cottingham, Karen L.; Garetto, Lawrence P.; Burr, David B.; Crow, Heidi; Katona, Thomas R.; Shanks, JamesBisphosphonates, drugs which inhibit bone resorption and remodeling, are currently prescribed for the treatment of osteoporosis. Previous research suggests that decreased bone turnover may lead to accumulation of microdamage, possibly increasing the risk for fracture in some sites. The effects of bisphosphonate therapy on the mandibular condyle have not been quantitatively studied. The purpose of the proposed study was to histomorphometrically quantify the effects of etidronate (a bisphosphonate) on trabecular bone sites of the dog mandibular condyle and to compare this to another trabecular bone site (vertebrae) to determine whether the two sites were affected differently. Eleven mature female dogs were treated with high- (5 mg/kg/d) and low- (0.5 mg/kg/d) dose etidronate therapy for seven months. Fluorochrome labels were used to mark sites of bone mineralization for the calculation of static and dynamic histomorphometric parameters. High-dose therapy resulted in a complete inhibition of remodeling, as shown by the reduction of mineral apposition rate (MAR), bone formation rate (BFR), and mineralizing surface (MS/BS) to zero. Low-dose therapy also decreased BFR and MS/BS. Osteoid accumulation was only significant in the high-dose therapy group, but there was no evidence of osteomalacia (osteoid volume < 5%). Etidronate treatment had no significant effect on bone volume, trabecular number, trabecular thickness, or trabecular separation. Vertebral trabeculae ranged from 5.5 to 9.5 times greater in number than mandibular trabeculae, but were 45 to 60 percent thinner and closer together. The interaction between dosage and site was insignificant for all parameters studied. Further investigation is needed to determine whether these effects will prove to be harmful to the mandibular condyle, especially over a long period of time.Item Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling(Spandidos Publications, 2018-09) Wang, Luqi; Wang, Yue; Chen, Andy; Jalali, Aydin; Liu, Shengzhi; Guo, Yunxia; Na, Sungsoo; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyChemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization.Item Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model(PLOS, 2017-08-09) Allen, Matthew R.; McNerny, Erin; Aref, Mohammad; Organ, Jason M.; Newman, Christopher L.; McGowan, Brian; Jang, Tim; Burr, David B.; Brown, Drew M.; Hammond, Max; Territo, Paul R.; Lin, Chen; Persohn, Scott; Jiang, Lei; Riley, Amanda A.; McCarthy, Brian P.; Hutchins, Gary D.; Wallace, Joseph M.; Anatomy and Cell Biology, School of MedicineA growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1–2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.Item Fluoride and Cortical Bone: A Histomorphometric Study in Rabbits(1997) Acon-Ng, Patricia; Garetto, Lawrence P.; Dunipace, Ann J.; Katona, Thomas R.; Shanks, James C.; Turner, Charles H.Fluoride has been used in the treatment of osteoporosis because of its apparent ability to directly initiate bone formation. However, fluoride's therapeutic efficacy is controversial. Clinical trials in the range of 50 to 75 mg/day demonstrated severe side effects and a lack of consistent therapeutic benefits. Animal studies have not fully proven a positive effect of fluoride on bone strength. The objective of this study was to determine the histomorphometric changes in the cortical bone of rabbits caused by high doses of fluoride. The hypothesis was that high-dose fluoride intake enhances bone modeling and inhibits bone remodeling. Twenty-four young adult (four months old) female, Dutch Belted rabbits were randomly divided in two groups. The control group received no fluoride in their drinking water, while the experimental group received 100-ppm fluoride. Both groups received approximately 12-ppm fluoride in their food. A pair of tetracycline labels was given two weeks apart before initiation of the experiment. Fluoride treatment was given for six months. A terminal pair of calcein green labels was given before the animals were euthanized. Histomorphometric measurements were made using stereological point-hit and linear-intercept methods. The histomorphometric findings were correlated with fluoride serum and bone levels and also with strength tests. The study demonstrated that fluoride increases bone modeling by increasing periosteal bone apposition and endosteal bone resorption. The net effect of fluoride was an enlargement of the cortical bone and bone marrow and, therefore, the total tissue cross-section. However, the observed increase in bone mass produced by fluoride did not have a positive effect on the mechanical properties of bone. Fluoride did not produce a change in the primary histomorphometric parameters of osteoid surface (OS/BS%) or mineralizing surface (MS/BS%). Fluoride treatment produced an increase in the cortical periosteal modified mineral apposition rate (CPMAR). The remaining dynamic indices (i.e. endosteal MAR, remodeling MAR, cortical endosteal BFR and total BFR, activation frequency and formation period) were not affected by fluoride. The study failed to show an inhibitory effect of fluoride on bone remodeling.Item TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone(Nature Research, 2019-03-22) Saito, Hiroaki; Gasser, Andreas; Bolamperti, Simona; Maeda, Miki; Matthies, Levi; Jähn, Katharina; Long, Courtney L.; Schlüter, Hartmut; Kwiatkowski, Marcel; Saini, Vaibhav; Pajevic, Paola Divieti; Bellido, Teresita; Wijnen, Andre J. van; Mohammad, Khalid S.; Guise, Theresa A.; Taipaleenmäki, Hanna; Hesse, Eric; Anatomy and Cell Biology, School of MedicineOsteoporosis is caused by increased bone resorption and decreased bone formation. Intermittent administration of a fragment of Parathyroid hormone (PTH) activates osteoblast-mediated bone formation and is used in patients with severe osteoporosis. However, the mechanisms by which PTH elicits its anabolic effect are not fully elucidated. Here we show that the absence of the homeodomain protein TG-interacting factor 1 (Tgif1) impairs osteoblast differentiation and activity, leading to a reduced bone formation. Deletion of Tgif1 in osteoblasts and osteocytes decreases bone resorption due to an increased secretion of Semaphorin 3E (Sema3E), an osteoclast-inhibiting factor. Tgif1 is a PTH target gene and PTH treatment failed to increase bone formation and bone mass in Tgif1-deficient mice. Thus, our study identifies Tgif1 as a novel regulator of bone remodeling and an essential component of the PTH anabolic action. These insights contribute to a better understanding of bone metabolism and the anabolic function of PTH.