IU Indianapolis ScholarWorks :: Browsing by Author "Organ, Jason M."

Browsing by Author "Organ, Jason M."

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Anatomy Nights: An international public engagement event increases audience knowledge of brain anatomy
(PLOS, 2022-06-09) Sanders, Katherine A.; Philp, Janet A.C.; Jordan, Crispin Y.; Cale, Andrew S.; Cunningham, Claire L.; Organ, Jason M.; Anatomy, Cell Biology and Physiology, School of Medicine
Anatomy Nights is an international public engagement event created to bring anatomy and anatomists back to public spaces with the goal of increasing the public's understanding of their own anatomy by comparison with non-human tissues. The event consists of a 30-minute mini-lecture on the anatomy of a specific anatomical organ followed by a dissection of animal tissues to demonstrate the same organ anatomy. Before and after the lecture and dissection, participants complete research surveys designed to assess prior knowledge and knowledge gained as a result of participation in the event, respectively. This study reports the results of Anatomy Nights brain events held at four different venues in the UK and USA in 2018 and 2019. Two general questions were asked of the data: 1) Do participant post-event test scores differ from pre-event scores; and 2) Are there differences in participant scores based on location, educational background, and career. We addressed these questions using a combination of generalized linear models (R's glm function; R version 4.1.0 [R Core Team, 2014]) that assumed a binomial distribution and implemented a logit link function, as well as likelihood estimates to compare models. Survey data from 91 participants indicate that scores improve on post-event tests compared to pre-event tests, and these results hold irrespective of location, educational background, and career. In the pre-event tests, participants performed well on naming structures with an English name (frontal lobe and brainstem), and showed signs of improvement on other anatomical names in the post-test. Despite this improvement in knowledge, we found no evidence that participation in Anatomy Nights improved participants' ability to apply this knowledge to neuroanatomical contexts (e.g., stroke).
Anti-Sclerostin Antibody Treatment in a Rat Model of Progressive Renal Osteodystrophy
(2014-11-18) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Organ, Jason M.; Kneissel, Michaela; Kramer, Ina; Gattone II, Vincent H.; Allen, Matthew R.
Chronic Kidney Disease (CKD) is associated with abnormalities in bone quantity and quality leading to increased fractures. Recent studies suggest abnormalities of Wnt signaling in animal models of CKD and elevated sclerostin levels in patients with CKD. The goal of this study was to evaluate the effectiveness of anti-sclerostin antibody treatment in an animal model of progressive CKD with low and high parathyroid hormone (PTH) levels. Cy/+ male rats (CKD) were treated without or with calcium in the drinking water at 25 weeks of age to stratify the animals into high PTH and low PTH groups, respectively, by 30 weeks. Animals were then treated with anti-sclerostin antibody at 100 mg/kg IV weekly for 5 doses, a single 20 ug/kg subcutaneous dose of zoledronic acid, or no treatment and sacrificed at 35 weeks. As a positive control, the efficacy of anti-sclerostin antibody treatment was also evaluated in normal littermates. The results demonstrated that the CKD animals with high PTH had lower calcium, higher phosphorus, and lower FGF23 compared to the CKD animals with low PTH. Treatment with anti-sclerostin Ab had no effect on any of the biochemistries, while zoledronic acid lowered dkk-1 levels. The anti-sclerostin antibody increased trabecular BV/TV., trabecular mineralization surface, in animals with low, but not high, PTH. Neither anti-sclerostin antibody nor zoledronic acid improved biomechanical properties in the animals. Cortical porosity was severe in high PTH animals and unaffected by either treatment. In contrast, in normal animals treated with anti-sclerostin antibody, there was an improvement in bone volume, cortical geometry, and biomechanical properties. In summary, this is the first study to test the efficacy of anti-sclerostin Ab treatment on animals with advanced CKD. We found efficacy in improving bone properties only when the PTH levels were low.
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 Medicine
The 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.
Bone Perfusion Alterations in Chronic Kidney Disease
(2019-05) Aref, Mohammad W.; Allen, Matthew R.; Organ, Jason M.; Tune, Jonathan D.; Wallace, Joseph M.; Moe, Sharon M.
Patients with chronic kidney disease (CKD) are at an alarming risk of fracture and cardiovascular disease-associated mortality. There is a critical need to better understand the underlying mechanism driving altered cardiovascular and skeletal homeostasis, as well as any connection between the two. CKD has been shown to have negative effects on many vascular properties including endorgan perfusion. Surprisingly, exploration of skeletal perfusion and vasculature has not been undertaken in CKD. Alterations in bone perfusion are linked to dysregulation of bone remodeling and mass in multiple conditions. An understanding of the detrimental impact of CKD on bone perfusion is a crucial step in understanding bone disease in these patients. The goal of this series of studies was to test the global hypothesis that skeletal perfusion is altered in CKD and that alterations can be modulated through treatments that affect metabolic dysfunction. These studies utilized a rat model of CKD to conduct metabolic assessments, bone perfusion measurements, bone imaging studies, and isolated vessel reactivity experiments. Our results showed that animals with CKD had higher levels of parathyroid hormone (PTH), leading to substantial bone resorption. Bone perfusion measurements showed CKD-induced elevations in cortical bone perfusion with levels progressing alongside CKD severity. Conversely we show that marrow perfusion was lower in advanced CKD. PTH suppression therapy in animals with CKD resulted in the normalization of cortical bone perfusion and cortical bone mass, but did not normalize marrow bone perfusion. These results show a clear association between bone deterioration and altered bone perfusion in CKD. While the relationship of altered bone perfusion and bone deterioration in CKD necessitates further work, these results indicate that determining the mechanisms of bone perfusion alterations and whether they are drivers, propagators, or consequences of skeletal deterioration in CKD could help untangle a key player in CKD-induced bone alterations.
A case for using eponyms in anatomy to teach bioethics
(American Association for Anatomy, 2021-11) Organ, Jason M.; Mussell, Jason C.; Anatomy and Cell Biology, School of Medicine
Caudal Vertebral Body Articular Surface Morphology Correlates with Functional Tail Use in Anthropoid Primates
(http://onlinelibrary.wiley.com/doi/10.1002/jmor.20304/abstract, 2014) Deane, Andrew S.; Russo, Gabrielle A.; Muchlinski, Magdalena N.; Organ, Jason M.
Prehensile tails, capable of suspending the entire body weight of an animal, have evolved in parallel in New World monkeys (Platyrrhini): once in the Atelinae (Alouatta, Ateles, Brachyteles, Lagothrix), and once in the Cebinae (Cebus, Sapajus). Structurally, the prehensile tails of atelines and cebines share morphological features that distinguish them from non-prehensile tails, including longer proximal tail regions, well-developed hemal processes, robust caudal vertebrae resistant to higher torsional and bending stresses, and caudal musculature capable of producing higher contractile forces. The functional significance of shape variation in the articular surfaces of caudal vertebral bodies, however, is relatively less well understood. Given that tail use differs considerably among prehensile and non-prehensile anthropoids, it is reasonable to predict that caudal vertebral body articular surface area and shape will respond to use-specific patterns of mechanical loading. We examine the potential for intervertebral articular surface contour curvature and relative surface area to discriminate between prehensile- and nonprehensile-tailed platyrrhines and cercopithecoids. The proximal and distal intervertebral articular surfaces of the first (Ca1), transitional (TV) and longest (LV) caudal vertebrae were examined for individuals representing 10 anthropoid taxa with differential patterns of tail-use. Study results reveal significant morphological differences consistent with the functional demands of unique patterns of tail use for all vertebral elements sampled. Prehensile-tailed platyrrhines that more frequently use their tails in suspension (atelines) had significantly larger and more convex intervertebral articular surfaces than all nonprehensile-tailed anthropoids examined here, although the intervertebral articular surface contour curvatures of large, terrestrial cercopithecoids (i.e. Papio) converge on the ateline condition. Prehensile-tailed platyrrhines that more often use their tails in tripodal bracing postures (cebines) are morphologically intermediate between atelines and nonprehensile tailed anthropoids.
A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD
(Wiley, 2014-04) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone II, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.; Department of Medicine, IU School of Medicine
Patients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about oversuppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for 10 weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by micro-computed tomography (µCT) and both equally suppressed the mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.
A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD
(Published article can be found at: http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2089/abstract doi: 10.1002/jbmr.2089, 2013-09-03) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone II, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.
Patients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about over-suppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for ten weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by microCT and both equally suppressed mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.
Disabling the Transcription Factor Nmp4 from Osteogenic Precursors Enhances the Skeleton's Response to the Osteoporosis Drug Parathyroid Hormone
(2022-08) Atkinson, Emily Grace; Bidwell, Joseph P.; Robling, Alexander G.; Plotkin, Lilian I.; Wallace, Joseph; Organ, Jason M.; Evans-Molina, Carmella
Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis. Yet, FDA-approved osteoanabolics, e.g., parathyroid hormone (PTH) have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice, exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues, therefore, to determine whether the suppression of PTHinduced bone formation is cell autonomous, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts and (iii) Dmp1Cre+ to disable Nmp4 in transitional osteocytes. Virgin female Cre+ and Cre- mice (10wks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1–34 at 30μg/kg, or vehicle for 4wks or 7wks. The skeletal response was assessed using dual-energy X-ray absorptiometry, microcomputed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl;Prx1Cre+ mice recapitulated the global Nmp4-/- skeletal phenotype in the femur, i.e., an enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared to their Nmp4fl/fl;Prx1Cre- controls. This was not observed in the spine, where Prx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl;BglapCre+) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl;Dmp1Cre+) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4-/- MSPCs drive the enhanced response to PTH therapy, and Nmp4 has stage-specific effects on osteoanabolism.
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 Medicine
A 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.

Browsing by Author "Organ, Jason M."

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