Browsing by Author "Gautam, Aarti"
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Item Analysis of the effects of spaceflight and local administration of thrombopoietin to a femoral defect injury on distal skeletal sites(Springer Nature, 2021-03-26) Zamarioli, Ariane; Campbell, Zachery R.; Maupin, Kevin A.; Childress, Paul J.; Ximenez, Joao P.B.; Adam, Gremah; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineWith increased human presence in space, bone loss and fractures will occur. Thrombopoietin (TPO) is a recently patented bone healing agent. Here, we investigated the systemic effects of TPO on mice subjected to spaceflight and sustaining a bone fracture. Forty, 9-week-old, male, C57BL/6 J were divided into 4 groups: (1) Saline+Earth; (2) TPO + Earth; (3) Saline+Flight; and (4) TPO + Flight (n = 10/group). Saline- and TPO-treated mice underwent a femoral defect surgery, and 20 mice were housed in space ("Flight") and 20 mice on Earth for approximately 4 weeks. With the exception of the calvarium and incisor, positive changes were observed in TPO-treated, spaceflight bones, suggesting TPO may improve osteogenesis in the absence of mechanical loading. Thus, TPO, may serve as a new bone healing agent, and may also improve some skeletal properties of astronauts, which might be extrapolated for patients on Earth with restraint mobilization and/or are incapable of bearing weight on their bones.Item The effects of spaceflight and fracture healing on distant skeletal sites(Springer Nature, 2019-08-06) Dadwal, Ushashi C.; Maupin, Kevin A.; Zamarioli, Ariane; Tucker, Aamir; Harris, Jonathan S.; Fischer, James P.; Rytlewski, Jeffery D.; Scofield, David C.; Wininger, Austin E.; Bhatti, Fazal Ur Rehman; Alvarez, Marta; Childress, Paul J.; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineSpaceflight results in reduced mechanical loading of the skeleton, which leads to dramatic bone loss. Low bone mass is associated with increased fracture risk, and this combination may compromise future, long-term, spaceflight missions. Here, we examined the systemic effects of spaceflight and fracture surgery/healing on several non-injured bones within the axial and appendicular skeleton. Forty C57BL/6, male mice were randomized into the following groups: (1) Sham surgery mice housed on the earth (Ground + Sham); (2) Femoral segmental bone defect surgery mice housed on the earth (Ground + Surgery); (3) Sham surgery mice housed in spaceflight (Flight + Sham); and (4) Femoral segmental bone defect surgery mice housed in spaceflight (Flight + Surgery). Mice were 9 weeks old at the time of launch and were euthanized approximately 4 weeks after launch. Micro-computed tomography (μCT) was used to evaluate standard bone parameters in the tibia, humerus, sternebra, vertebrae, ribs, calvarium, mandible, and incisor. One intriguing finding was that both spaceflight and surgery resulted in virtually identical losses in tibial trabecular bone volume fraction, BV/TV (24-28% reduction). Another important finding was that surgery markedly changed tibial cortical bone geometry. Understanding how spaceflight, surgery, and their combination impact non-injured bones will improve treatment strategies for astronauts and terrestrial humans alike.Item Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight(Elsevier, 2021-06-08) Chakraborty, Nabarun; Zamarioli, Ariane; Gautam, Aarti; Campbell, Ross; Mendenhall, Stephen K.; Childress, Paul J.; Dimitrov, George; Sowe, Bintu; Tucker, Aamir; Zhao, Liming; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineAdverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.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 Skeletal adaptations in young male mice after 4 weeks aboard the International Space Station(Nature Research, 2019-09-24) Maupin, Kevin A.; Childress, Paul; Brinker, Alexander; Khan, Faisal; Abeysekera, Irushi; Aguilar, Izath Nizeet; Olivos, David J., III; Adam, Gremah; Savaglio, Michael K.; Ganesh, Venkateswaran; Gorden, Riley; Mannfeld, Rachel; Beckner, Elliott; Horan, Daniel J.; Robling, Alexander G.; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineGravity has an important role in both the development and maintenance of bone mass. This is most evident in the rapid and intense bone loss observed in both humans and animals exposed to extended periods of microgravity in spaceflight. Here, cohabitating 9-week-old male C57BL/6 mice resided in spaceflight for ~4 weeks. A skeletal survey of these mice was compared to both habitat matched ground controls to determine the effects of microgravity and baseline samples in order to determine the effects of skeletal maturation on the resulting phenotype. We hypothesized that weight-bearing bones would experience an accelerated loss of bone mass compared to non-weight-bearing bones, and that spaceflight would also inhibit skeletal maturation in male mice. As expected, spaceflight had major negative effects on trabecular bone mass of the following weight-bearing bones: femur, tibia, and vertebrae. Interestingly, as opposed to the bone loss traditionally characterized for most weight-bearing skeletal compartments, the effects of spaceflight on the ribs and sternum resembled a failure to accumulate bone mass. Our study further adds to the insight that gravity has site-specific influences on the skeleton.Item Systemic effects of BMP2 treatment of fractures on non-injured skeletal sites during spaceflight(Frontiers Media, 2022-08-15) Zamarioli, Ariane; Adam, Gremah; Maupin, Kevin A.; Childress, Paul J.; Brinker, Alexander; Ximenez, Joao P. B.; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineUnloading associated with spaceflight results in bone loss and increased fracture risk. Bone morphogenetic protein 2 (BMP2) is known to enhance bone formation, in part, through molecular pathways associated with mechanical loading; however, the effects of BMP2 during spaceflight remain unclear. Here, we investigated the systemic effects of BMP2 on mice sustaining a femoral fracture followed by housing in spaceflight (International Space Station or ISS) or on Earth. We hypothesized that in spaceflight, the systemic effects of BMP2 on weight-bearing bones would be blunted compared to that observed on Earth. Nine-week-old male mice were divided into four groups: 1) Saline+Earth; 2) BMP+Earth; 3) Saline+ISS; and 4) BMP+ISS (n = 10 mice/group, but only n = 5 mice/group were reserved for micro-computed tomography analyses). All mice underwent femoral defect surgery and were followed for approximately 4 weeks. We found a significant reduction in trabecular separation within the lumbar vertebrae after administering BMP2 at the fracture site of mice housed on Earth. In contrast, BMP2 treatment led to a significant increase in trabecular separation concomitant with a reduction in trabecular number within spaceflown tibiae. Although these and other lines of evidence support our hypothesis, the small sample size associated with rodent spaceflight studies limits interpretations. That said, it appears that a locally applied single dose of BMP2 at the femoral fracture site can have a systemic impact on distant bones, affecting bone quantity in several skeletal sites. Moreover, our results suggest that BMP2 treatment works through a pathway involving mechanical loading in which the best outcomes during its treatment on Earth occurred in the weight-bearing bones and in spaceflight occurred in bones subjected to higher muscle contraction.Item Thrombopoietic agents enhance bone healing in mice, rats, and pigs(Oxford University Press, 2024) Childress, Paul J.; Nielsen, Jeffery J.; Bemenderfer, Thomas B.; Dadwal, Ushashi C.; Chakraborty, Nabarun; Harris, Jonathan S.; Bethel, Monique; Alvarez, Marta B.; Tucker, Aamir; Wessel, Alexander R.; Millikan, Patrick D.; Wilhite, Jonathan H.; Engle, Andrew; Brinker, Alexander; Rytlewski, Jeffrey D.; Scofield, David C.; Griffin, Kaitlyn S.; Shelley, W. Christopher; Manikowski, Kelli J.; Jackson, Krista L.; Miller, Stacy-Ann; Cheng, Ying-Hua; Ghosh, Joydeep; Mulcrone, Patrick L.; Srour, Edward F.; Yoder, Mervin C.; Natoli, Roman M.; Shively, Karl D.; Gautam, Aarti; Hammamieh, Rasha; Low, Stewart A.; Low, Philip S.; McKinley, Todd O.; Anglen, Jeffrey O.; Lowery, Jonathan W.; Chu, Tien-Min G.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineAchieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte (MK) growth factor, thrombopoietin (TPO), and second-generation TPO agents using multiple animal models, including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical-sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (eg, thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.