IU Indianapolis ScholarWorks :: Browsing by Author "Fuchs, Robyn K."

Browsing by Author "Fuchs, Robyn K."

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17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension
(APS Journals, 2016-08-01) Lahm, Tim; Frump, Andrea L.; Albrecht, Marjorie E.; Fisher, Amanda J.; Cook, Todd G.; Jones, Thomas J.; Yakubov, Bakhtiyor; Whitson, Jordan; Fuchs, Robyn K.; Liu, Aiping; Chesler, Naomi C.; Brown, M. Beth; Medicine, School of Medicine
17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg−1·day−1) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.
Adaptation of the proximal humerus to physical activity: a within-subject controlled study in baseball players
(Elsevier, 2019-01-08) Warden, Stuart J.; Carballido-Gamio, Julio; Avin, Keith G.; Kersh, Mariana E.; Fuchs, Robyn K.; Krug, Roland; Bice, Ryan; Physical Therapy, School of Health and Human Sciences
The proximal humerus is a common, yet understudied site for osteoporotic fracture. The current study explored the impact of prolonged physical activity on proximal humerus bone health by comparing bone properties between the throwing and nonthrowing arms within professional baseball players. The proximal humerus in throwing arms had 28.1% (95% CI, 17.8 to 38.3%) greater bone mass compared to nonthrowing arms, as assessed using dual-energy x-ray absorptiometry. At the level of the surgical neck, computed tomography revealed 12.0% (95% CI, 8.2 to 15.8%) greater total cross-sectional area and 31.0% (95% CI, 17.8 to 44.2%) greater cortical thickness within throwing arms, which contributed to 56.8% (95% CI, 44.9 to 68.8%) greater polar moment of inertia (i.e., estimated ability to resist torsional forces) compared to nonthrowing arms. Within the humeral head and greater tubercle regions, throwing arms had 3.1% (95% CI, 1.1 to 5.1%) more trabecular bone, as assessed using high-resolution magnetic resonance imaging. Three-dimensional mapping of voxel- and vertex-wise differences between arms using statistical parametric mapping techniques revealed throwing arms had adaptation within much of the proximal diaphysis, especially the posterolateral cortex. The pattern of proximal diaphysis adaptation approximated the pattern of strain energy distribution within the proximal humerus during a fastball pitch derived from a musculoskeletal and finite element model in a representative player. These data demonstrate the adaptive ability of the proximal humerus to physical activity-related mechanical loads. It remains to be established how they translate to exercise prescription to improve bone health within the proximal humerus, however, they provide unique insight into the relationship between prolonged loading and skeletal adaptation at a clinically relevant osteoporotic site.
Age-Related Changes in Proximal Humerus Bone Health in White Males
(Office of the Vice Chancellor for Research, 2012-04-13) Fuchs, Robyn K.; Mantila Roosa, Sara M.; Hurd, Andrea L; Warden, Stuart J.
The proximal humerus is a common site for osteoporotic fracture during aging, accounting for up to 5% of fractures to the appendicular skeleton. While falls onto an outstretched hand are usually physically responsible for proximal humerus fractures, the ability of the underlying bone to resist applied loads must also play a role. Few studies have assessed proximal humerus bone health with aging. The aim of the current study was to explore age-related bone changes at the proximal humerus in men. A cross-sectional study design was used to assess peripheral quantitative computed tomography (pQCT)-derived bone properties of the proximal humerus in a cohort of 112 white males (age range = 30-85 yrs). A tomographic slice of the non-dominant upper extremity was acquired at 80% of humeral length proximal from its distal end—a location corresponding to the surgical neck of the humerus. Images were assessed for cortical (Ct.BMC) and trabecular (Tb.BMC) BMC, total (Tt.Ar), cortical (Ct.Ar) and medullary (Me.Ar) area, periosteal (Ps.Pm) and endosteal (Es.Pm) perimeter, cortical thickness (Ct.Th), and bone strength index for compression (BSIc). BSIc was calculated as the product of Tt.Ar and the square of total volumetric BMD. Data were plotted against age and linear regression lines assessed for their slope. Slopes were subsequently converted to percent change in the bone property per year. During aging, the proximal humerus expanded with Tt.Ar and Ps.Pm increasing at rates of 0.40%/yr and 0.19%/yr, respectively. However, Me.Ar (0.62%/yr) and Es.Pm (0.34%/yr) expanded at faster rates such that there was net loss of both Ct.BMC (-0.23%/yr) and Tb.BMC (-1.08%/yr). Also, the more rapid expansion of Me.Ar relative to Tt.Ar meant that Ct.Ar (-0.15%/yr) and Ct.Th (-0.34%/yr) both decreased with age. The net result of these mass and structural changes was progressive loss of bone strength with age, as indicated by a 0.44%/yr decline in BSIc. These data provide a picture of bone changes at the proximal humerus during aging. They suggest that between age 30 and 80 yrs, approximately 54% and 11% of Tb.BMC and Ct.BMC at the proximal humerus is lost, respectively. They also suggest that compressive strength of the proximal humerus declines by 22% between age 30 and 80 years. These declines in proximal humerus bone health have implications for fracture risk at this location during aging.
Am I big boned? Bone length scaled reference data for HRpQCT measures of the radial and tibial diaphysis in White adults
(Elsevier, 2024-01-06) Warden, Stuart J.; Fuchs, Robyn K.; Liu, Ziyue; Toloday, Katelynn R.; Surowiec, Rachel; Moe, Sharon M.; Physical Therapy, School of Health and Human Sciences
Cross-sectional size of a long bone shaft influences its mechanical properties. We recently used high-resolution peripheral quantitative computed tomography (HRpQCT) to create reference data for size measures of the radial and tibial diaphyses. However, data did not take into account the impact of bone length. Human bone exhibits relatively isometric allometry whereby cross-sectional area increases proportionally with bone length. The consequence is that taller than average individuals will generally have larger z-scores for bone size outcomes when length is not considered. The goal of the current work was to develop a means of determining whether an individual's cross-sectional bone size is suitable for their bone length. HRpQCT scans performed at 30 % of bone length proximal from the distal end of the radius and tibia were acquired from 1034 White females (age = 18.0 to 85.3 y) and 392 White males (age = 18.4 to 83.6 y). Positive relationships were confirmed between bone length and cross-sectional areas and estimated mechanical properties. Scaling factors were calculated and used to scale HRpQCT outcomes to bone length. Centile curves were generated for both raw and bone length scaled HRpQCT data using the LMS approach. Excel-based calculators are provided to facilitate calculation of z-scores for both raw and bone length scaled HRpQCT outcomes. The raw z-scores indicate the magnitude that an individual's HRpQCT outcomes differ relative to expected sex- and age-specific values, with the scaled z-scores also considering bone length. The latter enables it to be determined whether an individual or population of interest has normal sized bones for their length, which may have implications for injury risk. In addition to providing a means of expressing HRpQCT bone size outcomes relative to bone length, the current study also provides centile curves for outcomes previously without reference data, including tissue mineral density and moments of inertia.
Baseball and softball pitchers are distinct within-subject controlled models for exploring proximal femur adaptation to physical activity
(Springer, 2019-01-21) Fuchs, Robyn K.; Thompson, William R.; Weatherholt, Alyssa M.; Warden, Stuart J.; Physical Therapy, School of Health and Human Sciences
Purpose: Within-subject controlled models in individuals who preferentially load one side of the body enable efficient exploration of the skeletal benefits of physical activity. There is no established model of physical activity-induced side-to-side differences (i.e., asymmetry) at the proximal femur. Methods: Proximal femur asymmetry was assessed via dual-energy x-ray absorptiometry in male jumping athletes (JMP, n=16), male baseball pitchers (BB, n=21), female fast-pitch softball pitchers (SB, n=22), and controls (CON, n=42). The jumping leg was the dominant leg in JMP, whereas in BB, SB and CON the dominant leg was contralateral to the dominant/throwing arm. Results: BB and SB had 5.5% (95%CI, 3.9 to 7.0%) and 6.5% (95%CI, 4.8 to 8.2%) dominant-to-nondominant leg differences for total hip areal bone mineral density (aBMD), with the asymmetry being greater than both CON and JMP (p<0.05). BB and SB also possessed dominant-to-nondominant leg differences in femoral neck and trochanteric aBMD (p<0.001). SB had 9.7% (95% CI, 6.4 to 13.0%) dominant-to-nondominant leg differences in femoral neck bone mineral content, which was larger than any other group (p≤0.006). At the narrow neck, SB had large (>8%) dominant-to-nondominant leg differences in cross-sectional area, cross-sectional moment of inertia and section modulus, which were larger than any other group (p≤0.02). Conclusion: Male baseball and female softball pitchers are distinct within-subject controlled models for exploring adaptation of the proximal femur to physical activity. They exhibit adaptation in their dominant/landing leg (i.e., leg contralateral to the throwing arm), but the pattern differs with softball pitchers exhibiting greater femoral neck adaptation.
Bone Microarchitecture and Strength Adaptation to Physical Activity: A Within-Subject Controlled, HRpQCT Study
(Wolters Kluwer, 2021) Warden, Stuart J.; Wright, Christian S.; Fuchs, Robyn K.; Physical Therapy, School of Health and Rehabilitation Sciences
Purpose Physical activity benefits bone mass and cortical bone size. The current study assessed the impact of chronic (≥10 years) physical activity on trabecular microarchitectural properties and micro-finite element (μFE) analyses of estimated bone strength. Methods Female collegiate-level tennis players (n=15; age=20.3±0.9 yrs) were used as a within-subject controlled model of chronic unilateral upper-extremity physical activity. Racquet-to-nonracquet arm differences at the distal radius and radial diaphysis were assessed using high-resolution peripheral computed tomography (HRpQCT). The distal tibia and tibial diaphysis in both legs were also assessed, and cross-country runners (n=15; age=20.8±1.2 yrs) included as controls. Results The distal radius of the racquet arm had 11.8% (95% confidence interval [CI], 7.9 to 15.7%) greater trabecular bone volume/tissue volume, with trabeculae that were greater in number, thickness, connectivity, and proximity to each other than in the nonracquet arm (all p<0.01). Combined with enhanced cortical bone properties, the microarchitectural advantages at the distal radius contributed a 18.7% (95% CI, 13.0 to 24.4%) racquet-to-nonracquet arm difference in predicted load before failure. At the radial diaphysis, predicted load to failure was 9.6% (95% CI, 6.7 to 12.6%) greater in the racquet vs. nonracquet arm. There were fewer and smaller side-to-side differences at the distal tibia; however, the tibial diaphysis in the leg opposite the racquet arm was larger with a thicker cortex and had 4.4% (95% CI, 1.7 to 7.1%) greater strength than the contralateral leg. Conclusion Chronically elevated physical activity enhances trabecular microarchitecture and μFE estimated strength, furthering observations from short-term longitudinal studies. The data also demonstrate tennis players exhibit crossed symmetry wherein the leg opposite the racquet arm possesses enhanced tibial properties compared to in the contralateral leg.
Bone Morphogenetic Protein-2 Rapidly Heals Two Distinct Critical Sized Segmental Diaphyseal Bone Defects in a Porcine Model
(Oxford University Press, 2023) McKinley, Todd O.; Childress, Paul; Jewell, Emily; Griffin, Kaitlyn S.; Wininger, Austin E.; Tucker, Aamir; Gremah, Adam; Savaglio, Michael K.; Warden, Stuart J.; Fuchs, Robyn K.; Natoli, Roman M.; Shively, Karl D.; Anglen, Jeffrey O.; Chu, Tien-Min Gabriel; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
Introduction: Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. Materials and methods: Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. Results: BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P < .0001). mRUST scores increased from 8.2 (±1.1) in ORIF40 Cont to 14.3 (±1.0) in ORIF40 BMP specimens (P < .01). CT scans confirmed all BMP-2 specimens had healed and none of the control specimens had healed in both IMN and ORIF groups. BMP-2 restored 114% and 93% of intact torsional stiffness in IMN25 BMP and ORIF40 BMP specimens. Conclusions: We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.
C-Mpl Is Expressed on Osteoblasts and Osteoclasts and Is Important in Regulating Skeletal Homeostasis
(Wiley, 2016-04) Meijome, Tomas E.; Baughman, Jenna T.; Hooker, R. Adam; Cheng, Ying-Hua; Ciovacco, Wendy A.; Balamohan, Sanjeev M.; Srinivasan, Trishya L.; Chitteti, Brahmananda R.; Eleniste, Pierre P.; Horowitz, Mark C.; Srour, Edward F.; Bruzzaniti, Angela; Fuchs, Robyn K.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
C-Mpl is the receptor for thrombopoietin (TPO), the main megakaryocyte (MK) growth factor, and c-Mpl is believed to be expressed on cells of the hematopoietic lineage. As MKs have been shown to enhance bone formation, it may be expected that mice in which c-Mpl was globally knocked out (c-Mpl(-/-) mice) would have decreased bone mass because they have fewer MKs. Instead, c-Mpl(-/-) mice have a higher bone mass than WT controls. Using c-Mpl(-/-) mice we investigated the basis for this discrepancy and discovered that c-Mpl is expressed on both osteoblasts (OBs) and osteoclasts (OCs), an unexpected finding that prompted us to examine further how c-Mpl regulates bone. Static and dynamic bone histomorphometry parameters suggest that c-Mpl deficiency results in a net gain in bone volume with increases in OBs and OCs. In vitro, a higher percentage of c-Mpl(-/-) OBs were in active phases of the cell cycle, leading to an increased number of OBs. No difference in OB differentiation was observed in vitro as examined by real-time PCR and functional assays. In co-culture systems, which allow for the interaction between OBs and OC progenitors, c-Mpl(-/-) OBs enhanced osteoclastogenesis. Two of the major signaling pathways by which OBs regulate osteoclastogenesis, MCSF/OPG/RANKL and EphrinB2-EphB2/B4, were unaffected in c-Mpl(-/-) OBs. These data provide new findings for the role of MKs and c-Mpl expression in bone and may provide insight into the homeostatic regulation of bone mass as well as bone loss diseases such as osteoporosis.
CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis
(BioMed Central, 2006-10-24) Sheridan, Carol; Kishimoto, Hiromitsu; Fuchs, Robyn K.; Mehrotra, Sanjana; Bhat-Nakshatri, Poornima; Turner, Charles H.; Goulet Jr., Robert; Badve, Sunil; Nakshatri, Harikrishna; Anatomy and Cell Biology, School of Medicine
Introduction A subpopulation (CD44+/CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis. Methods CD44 and CD24 expression was determined by flow cytometry. Northern blotting was used to determine the expression of proinvasive and 'bone and lung metastasis signature' genes. A matrigel invasion assay and intracardiac inoculation into nude mice were used to evaluate invasion, and homing and proliferation at sites of metastasis, respectively. Results Five among 13 breast cancer cell lines examined (MDA-MB-231, MDA-MB-436, Hs578T, SUM1315, and HBL-100) contained a higher percentage (>30%) of CD44+/CD24- cells. Cell lines with high CD44+/CD24- cell numbers express basal/mesenchymal or myoepithelial but not luminal markers. Expression levels of proinvasive genes (IL-1α, IL-6, IL-8, and urokinase plasminogen activator [UPA]) were higher in cell lines with a significant CD44+/CD24- population than in other cell lines. Among the CD44+/CD24--positive cell lines, MDA-MB-231 has the unique property of expressing a broad range of genes that favor bone and lung metastasis. Consistent with previous studies in nude mice, cell lines with CD44+/CD24- subpopulation were more invasive than other cell lines. However, only a subset of CD44+/CD24--positive cell lines was able to home and proliferate in lungs. Conclusion Breast cancer cells with CD44+/CD24- subpopulation express higher levels of proinvasive genes and have highly invasive properties. However, this phenotype is not sufficient to predict capacity for pulmonary metastasis.
Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage
(Wiley, 2016-06) Uzer, Gunes; Fuchs, Robyn K.; Rubin, Janet; Thompson, William R.; Department of Physical Therapy, School of Health and Rehabilitation Sciences
Numerous factors including chemical, hormonal, spatial, and physical cues determine stem cell fate. While the regulation of stem cell differentiation by soluble factors is well-characterized, the role of mechanical force in the determination of lineage fate is just beginning to be understood. Investigation of the role of force on cell function has largely focused on “outside-in” signaling, initiated at the plasma membrane. When interfaced with the extracellular matrix, the cell uses integral membrane proteins, such as those found in focal adhesion complexes to translate force into biochemical signals. Akin to these outside-in connections, the internal cytoskeleton is physically linked to the nucleus, via proteins that span the nuclear membrane. Although structurally and biochemically distinct, these two forms of mechanical coupling influence stem cell lineage fate and, when disrupted, often lead to disease. Here we provide an overview of how mechanical coupling occurs at the plasma and nuclear membranes. We also discuss the role of force on stem cell differentiation, with focus on the biochemical signals generated at the cell membrane and the nucleus, and how those signals influence various diseases. While the interaction of stem cells with their physical environment and how they respond to force is complex, an understanding of the mechanical regulation of these cells is critical in the design of novel therapeutics to combat diseases associated with aging, cancer, and osteoporosis.

Browsing by Author "Fuchs, Robyn K."

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