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Item 6'-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding(Elsevier, 2020-01-17) Powell, Katherine M.; Brown, Alexa P.; Skaggs, Cayla G.; Pulliam, Alexis N.; Berman, Alycia G.; Deosthale, Padmini; Plotkin, Lilian I.; Allen, Matthew R.; Williams, David R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and TechnologyRaloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/-) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/- mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.Item Assessing the inter- and intra-animal variability of in vivo OsteoProbe skeletal measures in untreated dogs(Elsevier, 2016-12) McNerny, Erin M.B.; Organ, Jason M.; Wallace, Joseph M.; Newman, Christopher L.; Brown, Drew M.; Allen, Matthew R.; Department of Anatomy and Cell Biology, School of MedicineThe OsteoProbe is a second-generation reference point indentation (RPI) device without a reference probe that is designed to simplify RPI testing for clinical use. Successful clinical implementation of the OsteoProbe would benefit from a better understanding of how its output, bone material strength index (BMSi), relates to the material properties of bone and under what conditions it reliably correlates with fracture risk. Large animal models have the potential to help fill this knowledge gap, as cadaveric studies are retrospective and limited by incomplete patient histories (including the potential use of bone matrix altering drugs such as bisphosphonates). The goal of this study was to assess the intra and inter-animal variability of OsteoProbe measures in untreated beagle dogs (n = 12), and to evaluate this variability in comparison to traditional mechanical testing. OsteoProbe measurements were performed in vivo on the left tibia of each dog and repeated 6 months later on the day of sacrifice. Within-animal variation of BMSi (CV of 5–10 indents) averaged 8.9 and 9.0% at the first and second timepoints, respectively. In contrast, inter-animal variation of BMSi increased from 5.3% to 9.1%. The group variation of BMSi was on par with that of traditional 3-point mechanical testing; inter-animal variation was 10% for ultimate force, 13% for stiffness, and 12% for total work as measured on the femur. There was no significant change in mean BMSi after 6 months, but the individual change with time across the 12 dogs was highly variable, ranging from − 12.4% to + 21.7% (mean 1.6%, SD 10.6%). No significant correlations were found between in vivo tibia BMSi and femur mechanical properties measured by ex vivo 3-pt bending, but this may be a limitation of sample size or the tests being performed on different bones. No relationship was found between BMSi and tissue mineral density, but a strong positive correlation was found between BMSi and tibia cortical thickness (ρ = 0.706, p = 0.010). This report shows that while the OsteoProbe device has inter-individual variability quite similar to that of traditional mechanical testing, the longitudinal changes show high levels of heterogeneity across subjects. We further highlight the need for standardization in post-testing data processing and further study of the relationships between OsteoProbe and traditional mechanical testing.Item Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics(Springer, 2017-06) McNerny, Erin M.B.; Nickolas, Thomas L.; Medicine, School of MedicinePURPOSE OF REVIEW: In this paper, we review the epidemiology, diagnosis, and pathogenesis of fractures and renal osteodystrophy. RECENT FINDINGS: The role of bone quality in the pathogenesis of fracture susceptibility in chronic kidney disease (CKD) is beginning to be elucidated. Bone quality refers to bone material properties, such as cortical and trabecular microarchitecture, mineralization, turnover, microdamage, and collagen content and structure. Recent data has added to our understanding of the effects of CKD on alterations to bone quality, emerging data on the role of abnormal collagen structure on bone strength, the potential of non-invasive methods to inform our knowledge of bone quality, and how we can use these methods to inform strategies that protect against bone loss and fractures. However, more prospective data is required. CKD is associated with abnormal bone quality and strength which results in high fracture incidence.Item Calcimimetics Alter Periosteal and Perilacunar Bone Matrix Composition and Material Properties in Early Chronic Kidney Disease(Wiley, 2022) Damrath, John G.; Moe, Sharon M.; Wallace, Joseph M.; Medicine, School of MedicineChronic kidney disease (CKD) affects 15% of Americans and greatly increases fracture risk due to elevated parathyroid hormone, cortical porosity, and reduced bone material quality. Calcimimetic drugs are used to lower parathyroid hormone (PTH) in CKD patients, but their impact on bone matrix properties remains unknown. We hypothesized that tissue-level bone quality is altered in early CKD and that calcimimetic treatment will prevent these alterations. To test this hypothesis, we treated Cy/+ rats, a model of spontaneous and progressive CKD-mineral and bone disorder (CKD-MBD), with KP-2326, a preclinical analogue of etelcalcetide, early in the CKD disease course. To measure tissue-level bone matrix composition and material properties, we performed colocalized Raman spectroscopy and nanoindentation on new periosteal bone and perilacunar bone using hydrated femur sections. We found that CKD and KP treatment lowered mineral type B carbonate substitution whereas KP treatment increased mineral crystallinity in new periosteal bone. Reduced elastic modulus was lower in CKD but was not different in KP-treated rats versus CTRL. In perilacunar bone, KP treatment lowered type B carbonate substitution, increased crystallinity, and increased mineral-to-matrix ratio in a spatially dependent manner. KP treatment also increased reduced elastic modulus and hardness in a spatially dependent manner. Taken together, these data suggest that KP treatment improves material properties on the tissue level through a combination of lowering carbonate substitution, increasing mineral crystallinity, and increasing relative mineralization of the bone early in CKD. As a result, the mechanical properties were improved, and in some regions, were the same as control animals. Therefore, calcimimetics may help prevent CKD-induced bone deterioration by improving bone quality in new periosteal bone and in bone tissue near osteocyte lacunae.Item Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4(Springer Nature, 2021-05-24) Fan, Yao; Zha, Rongrong; Sano, Tomohiko; Zhao, Xinyu; Liu, Shengzhi; Woollam, Mark D.; Wu, Di; Sun, Xun; Li, Kexin; Egi, Motoki; Li, Fangjia; Minami, Kazumasa; Siegel, Amanda P.; Horiuchi, Takashi; Liu, Jing; Agarwal, Mangilal; Sudo, Akihiro; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyMechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.Item Raloxifene improves bone mechanical properties in mice previously treated with zoledronate(SpringerLink, 2017-07) Meixner, Cory N.; Aref, Mohammad W.; Gupta, Aryaman; McNerny, Erin M.B.; Brown, Drew; Wallace, Joseph M.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineBisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.Item Targeting Bone Quality in Murine Models of Osteogenesis Imperfecta, Diabetes, and Chronic Kidney Disease(2024-05) Kohler, Rachel; Wallace, Joseph; Allen, Matthew; Bidwell, Joseph; Surowiec, RachelSkeletal fragility can be caused by a wide array of diseases and disorders, but the most difficult etiologies to clinically circumvent are those in which the body loses not just bone mass but the ability to create healthy bone tissue. While in conditions such as osteoporosis (the most prevalent cause of age-related skeletal fragility in which elevated resorption without compensatory elevated formation leads to bone loss), interventions can target bone remodeling pathways to protect and increase bone mass, many other diseases are characterized by genetic and metabolic crippling of the remodeling process, rendering those same mass-based interventions less effective at reducing fracture risk. Osteogenesis imperfecta (OI) is a class of genetic disorders in which gene mutations affect the formation of collagen, a crucial building block of bone tissue that makes up 90% of its organic matrix, leading to lost bone mass and quality. As the main genetic causes of OI cannot currently be directly treated, therapeutic OI treatments are needed that improve tissue-level material properties. Similarly, metabolic conditions such as diabetes, a disorder in which the body cannot properly regulate blood sugar due to loss of insulin production and/or efficacy, can have multi-organ impacts including increased risk of developing chronic kidney disease and skeletal fragility. Type 2 diabetes is especially notorious for increasing fracture risk despite maintained or even increased apparent bone mass, which is strong evidence that intrinsic bone material properties are impaired by the disease state. A possible solution to the bone quality problem may be treatments that increase bone water content, as amplifying the water content of bone can improve multi-scale material properties such as collagen fibril elasticity and whole-bone toughness. Therefore, increasing bone hydration could be a way of improving tissue-level material properties, despite being unable to eradicate the genetic or metabolic disorders that alter how collagen is produced and incorporated into the bone matrix. To that end, this dissertation presents several studies that characterize models of osteogenesis imperfecta and diabetic kidney disease in mice and investigate methods of rescuing skeletal fragility in these animals through treatments that target both bone mass and bone quality with ties to tissue hydration.Item Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone(Elsevier, 2019-10-01) Powell, Katherine M.; Skaggs, Cayla; Pulliam, Alexis; Berman, Alycia; Allen, Matthew R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and TechnologyCurrent interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties in a cell-independent manner by binding to collagen and increasing tissue hydration. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality. In this study, wildtype (WT) and heterozygous (OIM+/−) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or both from 8 weeks to 16 weeks of age. Using the OIM model allows for investigation of therapeutic effects on a quality-based bone disease. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, which are direct measures of the tissue's ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/− compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, trabecular bone volume fraction was significantly higher with combination treatment in both genotypes. Combination treatment resulted in higher ultimate stress in both genotypes. RAL and combination treatment in OIM+/− also increased resilience compared to the control. In conclusion, this study demonstrates the beneficial effects of using combination drug treatments to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a potential method to improve bone health and combat skeletal fragility on both the microscopic and macroscopic levels.