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Item A Healed Intertrochanteric Femur Fracture, Shoulder, and Rib Fractures in an Ancient Nubian Female: An Osteoarchaeological Perspective(Hindawi, 2024-02-12) Loder, Randall T.; Buzon, Michele R.; Sanders, Kaitlyn E.; Orthopaedic Surgery, School of MedicineThis report is a case of a healed proximal intertrochanteric femur fracture nonunion in an ancient Nubian adult female, approximately 58 years old at the time of death, from the Tombos archaeological site in present day northern Sudan. Tombos was founded as an Egyptian colonial town during the New Kingdom Period (14001070 BC). The individual was radiocarbon dated to 1114-910 BC and also exhibited healed fractures of the left proximal humerus and ribs. There was shortening and mild atrophy of the right femur compared to the left; radiographs demonstrated a varus deformity of the proximal femur with associated retroversion. Bone density analysis revealed that the tissue mineral density z-score for this individual was -0.798, with the z-score for Tombos females 15-24 years old being 0.396, or a total difference of 1.194. This indicates that the individual was osteopenic but not osteoporotic prior to demise. This is an important case as it occurred approximately 3000 years ago and is the oldest known reported case of a healed intertrochanteric hip fracture in the archaeological literature. Archaeological cases of intertrochanteric hip fractures are rare, with none previously reported from the BC era. The timing of these multiple fractures is unknown, but all healed before the demise of the individual. Thus, there must have been considerable care afforded to such an individual to minimize the morbidities associated with nonoperative care of such a fracture. If all these fractures occurred at the same time due to a traumatic, accidental injury, the Modified Injury Severity Score (MISS) would be 25. Modern day trauma resuscitation and orthopaedic care gives an estimated mortality for such a MISS score of 28% for those <50 years old. It is likely that this individual's high socioeconomic status allowed for intensive nursing care which likely decreased the morality risk.Item A Reproducible Cartilage Impact Model to Generate Post-Traumatic Osteoarthritis in the Rabbit(MyJove Corporation, 2023-11-21) Dilley, Julian; Noori-Dokht, Hessam; Seetharam, Abhijit; Bello, Margaret; Nanavaty, Aaron; Natoli, Roman M.; McKinley, Todd; Bault, Zachary; Wagner, Diane; Sankar, Uma; Anatomy, Cell Biology and Physiology, School of MedicinePost-traumatic osteoarthritis (PTOA) is responsible for 12% of all osteoarthritis cases in the United States. PTOA can be initiated by a single traumatic event, such as a high-impact load acting on articular cartilage, or by joint instability, as occurs with anterior cruciate ligament rupture. There are no effective therapeutics to prevent PTOA currently. Developing a reliable animal model of PTOA is necessary to better understand the mechanisms by which cartilage damage proceeds and to investigate novel treatment strategies to alleviate or prevent the progression of PTOA. This protocol describes an open, drop tower-based rabbit femoral condyle impact model to induce cartilage damage. This model delivered peak loads of 579.1 ± 71.1 N, and peak stresses of 81.9 ± 10.1 MPa with a time-to-peak load of 2.4 ± 0.5 ms. Articular cartilage from impacted medial femoral condyles (MFCs) had higher rates of apoptotic cells (p = 0.0058) and possessed higher Osteoarthritis Research Society International (OARSI) scores of 3.38 ± 1.43 compared to the non-impacted contralateral MFCs (0.56 ± 0.42), and other cartilage surfaces of the impacted knee (p < 0.0001). No differences in OARSI scores were detected among the non-impacted articular surfaces (p > 0.05).Item Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery(American Physiological Society, 2015-04-15) Prisby, Rhonda D.; Behnke, Bradley J.; Allen, Matthew R.; Delp, Michael D.; Department of Anatomy & Cell Biology, IU School of MedicineSpaceflight and prolonged bed rest induce deconditioning of the cardiovascular system and bone loss. Previous research has shown declines in femoral bone and marrow perfusion during unloading and with subsequent reloading in hindlimb-unloaded (HU) rats, an animal model of chronic disuse. We hypothesized that the attenuated bone and marrow perfusion may result from altered vasomotor properties of the bone resistance vasculature. Therefore, the purpose of this study was to determine the effects of unloading on the vasoconstrictor and vasodilator properties of the femoral principal nutrient artery (PNA), the main conduit for blood flow to the femur, in 2 wk HU and control (CON) rats. Vasoconstriction of the femoral PNA was assessed in vitro using norepinephrine, phenylephrine, clonidine, KCl, endothelin-1, arginine vasopressin, and myogenic responsiveness. Vasodilation through endothelium-dependent [acetylcholine, bradykinin, and flow-mediated dilation (FMD)] and endothelium-independent mechanisms [sodium nitroprusside (SNP) and adenosine] were also determined. Vasoconstrictor responsiveness of the PNA from HU rats was not enhanced through any of the mechanisms tested. Endothelium-dependent vasodilation to acetylcholine (CON, 86 ± 3%; HU, 48 ± 7% vasodilation) and FMD (CON, 61 ± 9%; HU, 11 ± 11% vasodilation) were attenuated in PNAs from HU rats, while responses to bradykinin were not different between groups. Endothelium-independent vasodilation to SNP and adenosine were not different between groups. These data indicate that unloading-induced decrements in bone and marrow perfusion and increases in vascular resistance are not the result of enhanced vasoconstrictor responsiveness of the bone resistance arteries but are associated with reductions in endothelium-dependent vasodilation.Item The Generation of Closed Femoral Fractures in Mice: A Model to Study Bone Healing(JoVE, 2018-08-16) Williams, Justin N.; Li, Yong; Kambrath, Anuradha Valiya; Sankar, Uma; Anatomy and Cell Biology, School of MedicineBone fractures impose a tremendous socio-economic burden on patients, in addition to significantly affecting their quality of life. Therapeutic strategies that promote efficient bone healing are non-existent and in high demand. Effective and reproducible animal models of fractures healing are needed to understand the complex biological processes associated with bone regeneration. Many animal models of fracture healing have been generated over the years; however, murine fracture models have recently emerged as powerful tools to study bone healing. A variety of open and closed models have been developed, but the closed femoral fracture model stands out as a simple method for generating rapid and reproducible results in a physiologically relevant manner. The goal of this surgical protocol is to generate unilateral closed femoral fractures in mice and facilitate a post-fracture stabilization of the femur by inserting an intramedullary steel rod. Although devices such as a nail or a screw offer greater axial and rotational stability, the use of an intramedullary rod provides a sufficient stabilization for consistent healing outcomes without producing new defects in the bone tissue or damaging nearby soft tissue. Radiographic imaging is used to monitor the progression of callus formation, bony union, and subsequent remodeling of the bony callus. Bone healing outcomes are typically associated with the strength of the healed bone and measured with torsional testing. Still, understanding the early cellular and molecular events associated with fracture repair is critical in the study of bone tissue regeneration. The closed femoral fracture model in mice with intramedullary fixation serves as an attractive platform to study bone fracture healing and evaluate therapeutic strategies to accelerate healing.Item Loss of STAT3 in osteoblasts has detrimental and sexually dimorphic effects on skeletal development(Public Library of Science, 2024-12-17) Davidson, Rebecca K.; Corry, Kylie; Orlofsky, Amos; Li, Ping; Russell, Caleb E.; Zhang, Amy; Moraes de Lima Perini, Mariana; Priddy, Carlie N.; Nguyen, Andrew V.; Li, Jiliang; Biology, School of ScienceStudies with genetically modified mice have implicated the transcriptional regulator STAT3 as a key modulator of bone development. STAT3-OKO knockout mouse lines were generated in two genetic backgrounds, pure C57BL/6 (STAT3-OKO-BL) and mixed C57BL/6, CD1 (STAT3-OKO-M). Both lines exhibited defective postnatal bone development resulting in reduced body weight and shortened femurs that displayed low bone mineral density as well as cortical widening and thinning in the diaphyseal region. Remarkably, each of these defects displayed sexual dimorphism that was dependent on genetic background: the phenotype was entirely male-specific in STAT3-OKO-M but not in STAT3-OKO-BL, in which defects were similar in both sexes. However, both lines exhibited a male-specific bone defect in mineralization, and also in bone mechanical properties related to bone quality, such as yield stress and ultimate stress. On the other hand, bone mechanical properties such as ultimate force, that may reflect density and macrostructure rather than bone quality, showed male-specific defects only in STAT3-OKO-M. These findings suggest that STAT3 may regulate multiple sex-dependent mechanisms in bone development that control either mineralization or bone accrual, and that the sex-dependence of at least some of these mechanisms is affected by genetic background. Finally, we used CRISPR/Cas9 to generate STAT3-deficient preosteoblastic cells from immortalized wild-type bone marrow stem cells and showed that the defective osteoblastic differentiation of STAT3-ablated cells was associated with reduced gene expression of Wnt3a and Wnt5a, consistent with other studies that identify Wnt signaling pathways as potential effector mechanisms for STAT3-mediated regulation of bone development.Item Microgravity's effects on miRNA-mRNA regulatory networks in a mouse model of segmental bone defects(Public Library of Science, 2024-12-02) Gautam, Aarti; Chakraborty, Nabarun; Dimitrov, George; Hoke, Allison; Miller, Stacy Ann; Swift, Kevin; Sowe, Bintu; Conley, Carolynn; Kacena, Melissa A.; Hammamieh, Rasha; Orthopaedic Surgery, School of MedicineRehabilitation from musculoskeletal injuries (MSKI) complicate healing dynamics typically by sustained disuse of bone and muscles. Microgravity naturally allows limb disuse and thus an effective model to understand MSKI. The current study examined epigenetic changes in a segmental bone defect (SBD) mouse model in a prolonged unloading condition after spaceflight (FLT). We further connected potential miRNA-mRNA regulatory pathways impacting bone healing. Here, SBD surgery was performed on nine-week-old male mice that were launched into space for approximately 4 weeks. Sham with no surgery and ground controls were included in the study. The midshaft of the ipsilateral femur (with callus on the surgical mice) as well as the ipsilateral quadriceps tissue were used for analysis. Femur and quadriceps had a distinct miRNA profile. There was a stronger surgery effect as observed by miRNA expression when compared to microgravity effects. Leukopoiesis, granulopoiesis, myelopoiesis of leukocytes, differentiation of myeloid leukocytes, and differentiation of progenitor cells were all altered because of surgery in the femur. The biological functions such as apoptosis, necrosis, and activation of cell migration and viability were altered because of surgery in quadriceps. Integrating the transcriptome and microRNA data indicated pronounced changes because of microgravity. According to pathway analysis, microgravity had a greater impact on the quadriceps tissue than the bone tissue in the absence of surgery. The altered biological functions resulting from microgravity were validated by integrating limited proteomics data to miRNA-mRNA. Thus, this study highlights the importance of dynamic interplay of gene-epigene regulations as they appear to be intrinsically interconnected and influence in combination for the biological outcome.Item Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH(Hindawi Publishing Corporation, 2015-01-28) Pacheco-Costa, Rafael; Campos, Jenifer Freitas; Katchburian, Eduardo; de Medeiros, Valquíria Pereira; Nader, Helena Bonciani; Nonaka, Keico Okino; Plotkin, Lilian Irene; Reginato, Rejane Daniele; Department of Anatomy & Cell Biology, IU School of MedicineBone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass.Item Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice(Oxford University Press, 2016-02) Alam, Imranul; Alkhouli, Mohammed; Gerard-O'Riley, Rita L.; Wright, Weston B.; Acton, Dena; Gray, Amie K.; Patel, Bhavmik; Reilly, Austin M.; Lim, Kyung-Eun; Robling, Alexander G.; Econs, Michael J.; Department of Medicine, IU School of MedicinePrevious genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified single nucleotide polymorphisms (SNPs) in Wingless-type mouse mammary tumor virus integration site (WNT)16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice overexpressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression, and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared with WT mice, WNT16-TG mice exhibited significantly higher whole-body areal BMD and bone mineral content (BMC) at 6 and 12 weeks of age in both male and female. Microcomputer tomography analysis of trabecular bone at distal femur revealed 3-fold (male) and 14-fold (female) higher bone volume/tissue volume (BV/TV), and significantly higher trabecular number and trabecular thickness but lower trabecular separation in TG mice compared with WT littermates in both sexes. The cortical bone at femur midshaft also displayed significantly greater bone area/total area and cortical thickness in the TG mice in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum alkaline phosphatase, osteocalcin, osteoprotegerin (OPG), OPG to receptor activator of NF-kB ligand (tumor necrosis family ligand superfamily, number 11; RANKL) ratio as compared with WT mice. Also, lower carboxy-terminal collagen cross-link (CTX) to tartrate-resistant acid phosphatase 5, isoform b (TRAPc5b) ratio was observed in TG mice compared with WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular mineralizing surface/bone surface and bone formation rate compared with sex-matched WT mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, and Opg to Rankl ratio in bone tissue in the TG mice compared with WT littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure and that this molecule might be targeted for therapeutic interventions to treat osteoporosis.Item Periprosthetic Fractures Around a Cementless Hydroxyapatite-coated Implant: A New Fracture Pattern Is Described(Springer US, 2014-02) Capello, William N.; D’Antonio, James A.; Naughton, Marybeth; Department of Orthopaedic Surgery, IU School of MedicineBackground Periprosthetic fractures can occur both intraoperatively and postoperatively with implantation of cementless tapered stems. Questions/purposes In a large cohort of patients receiving cementless, proximally hydroxyapatite-coated femoral implants, we answered the following questions: What was the incidence of intraoperative and postoperative fractures associated with the implant? What were the fracture patterns as classified by the Vancouver classification system? Did the Vancouver classification represent the fracture patterns found? How were the fractures treated and what were the treatment outcomes; that is, how many fractures healed and did the stems osseointegrate? Methods We evaluated 1039 hips (932 patients) from three prospective studies. The hips were divided into three groups: no fractures, intraoperative fractures, and postoperative fractures. Demographic differences among the groups were noted. Postoperative fractures were classified using the Vancouver classification system. We judged stem stability using Engh’s criteria and fracture union was determined by the treating surgeon and confirmed by the authors. Results We identified 58 periprosthetic fractures in the 1039 hips (5.6%): 38 intraoperative (3.7%) and 20 postoperative (1.9%). Eleven of the postoperative fractures were classifiable by the original Vancouver classification system and nine were of the newly described “clamshell” variety, not classifiable by this system. No intraoperative fractures extended below the lesser trochanter. Twenty-five of these fractures were treated with a single cable or cerclage wire. The remaining received no specific treatment. Of the 20 postoperative fractures, five were treated nonoperatively. All stems osseointegrated. Conclusions Both intraoperative and postoperative fractures can be managed with success when the stem is stabilized or found to be osseointegrated. An adjustment to the Vancouver classification is suggested to include the clamshell fracture, which has not been previously described. Level of Evidence Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.Item Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease(Nature Publishing Group, 2016-01) Newman, Christopher L.; Creecy, Amy; Granke, Mathilde; Nyman, Jeffry S.; Tian, Nannan; Hammond, Max A.; Wallace, Joseph M.; Brown, Drew M.; Chen, Neal; Moe, Sharon M.; Allen, Matthew R.; Department of Anatomy & Cell Biology, IU School of MedicinePatients with chronic kidney disease (CKD) have an increased risk of fracture. Raloxifene is a mild antiresorptive agent that reduces fracture risk in the general population. Here we assessed the impact of raloxifene on the skeletal properties of animals with progressive CKD. Male Cy/+ rats that develop autosomal dominant cystic kidney disease were treated with either vehicle or raloxifene for five weeks. They were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole-bone mechanics, and material properties). Their normal littermates served as controls. Animals with CKD had significantly higher parathyroid hormone levels compared with normal controls, as well as inferior structural and mechanical skeletal properties. Raloxifene treatment resulted in lower bone remodeling rates and higher cancellous bone volume in the rats with CKD. Although it had little effect on cortical bone geometry, it resulted in higher energy to fracture and modulus of toughness values than vehicle-treated rats with CKD, achieving levels equivalent to normal controls. Animals treated with raloxifene had superior tissue-level mechanical properties as assessed by nanoindentation, and higher collagen D-periodic spacing as assessed by atomic force microscopy. Thus, raloxifene can positively impact whole-bone mechanical properties in CKD through its impact on skeletal material properties.