Department of Physical Therapy Articles

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    Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation
    (MDPI, 2022-12-12) Reyes Fernandez, Perla C.; Wright, Christian S.; Masterson, Adrianna N.; Yi, Xin; Tellman, Tristen V.; Bonteanu, Andrei; Rust, Katie; Noonan, Megan L.; White, Kenneth E.; Lewis, Karl J.; Sankar, Uma; Hum, Julia M.; Bix, Gregory; Wu, Danielle; Robling, Alexander G.; Sardar, Rajesh; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human Sciences
    Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP.
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    Physical activity induced adaptation can increase proximal femur strength under loading from a fall onto the greater trochanter
    (Elsevier, 2021) Fuchs, Robyn K.; Carballido-Gamio, Julio; Keyak, Joyce H.; Kersh, Mariana E.; Warden, Stuart J.; Physical Therapy, School of Health and Human Sciences
    Physical activity enhances proximal femur bone mass, but it remains unclear whether the benefits translate into an enhanced ability to resist fracture related loading. We recently used baseball pitchers as a within-subject controlled model to demonstrate physical activity induced proximal femur adaptation in regions associated with weight bearing and increased strength under single-leg stance loading. However, there was no measurable benefit to resisting common injurious loading (e.g. a fall onto the greater trochanter). A lack of power and a small physical activity effect size may have contributed to the latter null finding. Softball pitchers represent an alternative within-subject controlled model to explore adaptation of the proximal femur to physical activity, exhibiting greater dominant-to-nondominant (D-to-ND) leg differences than baseball pitchers. The current study used quantitative computed tomography, statistical parametric mapping, and subject-specific finite element (FE) modeling to explore adaptation of the proximal femur to physical activity in female softball pitchers (n = 25). Female cross-country runners (n = 15) were included as symmetrically loaded controls, showing very limited D-to-ND leg differences. Softball pitchers had D-to-ND leg differences in proximal femur, femoral neck, and trochanteric volumetric bone mineral density and content, and femoral neck volume. Voxel-based morphometry analyses and cortical bone mapping showed D-to-ND leg differences within a large region connecting the superior femoral head, inferior femoral neck and medial intertrochanteric region, and within the greater trochanter. FE modeling revealed pitchers had 19.4% (95%CI, 15.0 to 23.9%) and 4.9% (95%CI, 1.7 to 8.2%) D-to-ND leg differences in predicted ultimate strength under single-leg stance loading and a fall onto the greater trochanter, respectively. These data affirm the spatial and strength adaptation of the proximal femur to weight bearing directed loading and demonstrate that the changes can also have benefits, albeit smaller, on resisting loads associated with a sideways fall onto the greater trochanter.
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    Preventing Bone Stress Injuries in Runners with Optimal Workload
    (Springer, 2021) Warden, Stuart J.; Edwards, W. Brent; Willy, Richard W.; Physical Therapy, School of Health and Human Sciences
    Bone stress injuries (BSIs) occur at inopportune times to invariably interrupt training. All BSIs in runners occur due to an "error" in workload wherein the interaction between the number and magnitude of bone tissue loading cycles exceeds the ability of the tissue to resist the repetitive loads. There is not a single optimal bone workload, rather a range which is influenced by the prevailing scenario. In prepubertal athletes, optimal bone workload consists of low-repetitions of fast, high-magnitude, multidirectional loads introduced a few times per day to induce bone adaptation. Premature sports specialization should be avoided so as to develop a robust skeleton that is structurally optimized to withstand multidirectional loading. In the mature skeleton, optimal workload enables gains in running performance but minimizes bone damage accumulation by sensibly progressing training, particularly training intensity. When indicated (e.g., following repeated BSIs), attempts to reduce bone loading magnitude should be considered, such as increasing running cadence. Determining the optimal bone workload for an individual athlete to prevent and manage BSIs requires consistent monitoring. In the future, it may be possible to clinically determine bone loads at the tissue level to facilitate workload progressions and prescriptions.
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    Effects of Dietary Protein Source and Quantity on Bone Morphology and Body Composition Following a High-Protein Weight-Loss Diet in a Rat Model for Postmenopausal Obesity
    (MDPI, 2022-05-28) Wright, Christian S.; Hill, Erica R.; Reyes Fernandez, Perla C.; Thompson, William R.; Gallant, Maxime A.; Campbell, Wayne W.; Main, Russell P.; Physical Therapy, School of Health and Human Sciences
    Higher protein (>30% of total energy, HP)-energy restriction (HP-ER) diets are an effective means to improve body composition and metabolic health. However, weight loss (WL) is associated with bone loss, and the impact of HP-ER diets on bone is mixed and controversial. Recent evidence suggests conflicting outcomes may stem from differences in age, hormonal status, and the predominant source of dietary protein consumed. Therefore, this study investigated the effect of four 12-week energy restriction (ER) diets varying in predominate protein source (beef, milk, soy, casein) and protein quantity (normal protein, NP 15% vs. high, 35%) on bone and body composition outcomes in 32-week-old obese, ovariectomized female rats. Overall, ER decreased body weight, bone quantity (aBMD, aBMC), bone microarchitecture, and body composition parameters. WL was greater with the NP vs. HP-beef and HP-soy diets, and muscle area decreased only with the NP diet. The HP-beef diet exacerbated WL-induced bone loss (increased trabecular separation and endocortical bone formation rates, lower bone retention and trabecular BMC, and more rod-like trabeculae) compared to the HP-soy diet. The HP-milk diet did not augment WL-induced bone loss. Results suggest that specific protein source recommendations may be needed to attenuate the adverse alterations in bone quality following an HP-ER diet in a model of postmenopausal obesity.
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    Physical Therapist Management of Patients With Suspected or Confirmed Osteoporosis: A Clinical Practice Guideline From the Academy of Geriatric Physical Therapy
    (Wolters Kluwer, 2022) Hartley, Gregory W.; Roach, Kathryn E.; Nithman, Robert W.; Betz, Sherri R.; Lindsey, Carleen; Fuchs, Robyn K.; Avin, Keith G.; Physical Therapy, School of Health and Human Sciences
    A clinical practice guideline on physical therapist management of patients with suspected or confirmed osteoporosis was developed by a volunteer guideline development group (GDG) that was appointed by the Academy of Geriatric Physical Therapy (APTA Geriatrics). The GDG consisted of an exercise physiologist and 6 physical therapists with clinical and methodological expertise. The guideline was based on a systematic review of existing clinical practice guidelines, followed by application of the ADAPTE methodological process described by Guidelines International Network for adapting guidelines for cultural and professional utility. The recommendations contained in this guideline are derived from the 2021 Scottish Intercollegiate Guideline Network (SIGN) document: Management of Osteoporosis and the Prevention of Fragility Fractures. These guidelines are intended to assist physical therapists practicing in the United States, and implementation in the context of the US health care system is discussed.
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    Skeletal Functions of Voltage Sensitive Calcium Channels
    (Springer, 2021) Wright, Christian S.; Robling, Alexander G.; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human Sciences
    Voltage-sensitive calcium channels (VSCCs) are ubiquitous multimeric protein complexes that are necessary for the regulation of numerous physiological processes. VSCCs regulate calcium influx and various intracellular processes including muscle contraction, neurotransmission, hormone secretion, and gene transcription, with function specificity defined by the channel‟s subunits and tissue location. The functions of VSCCs in bone are often overlooked since bone is not considered an electrically excitable tissue. However, skeletal homeostasis and adaptation relies heavily on VSCCs. Inhibition or deletion of VSCCs decreases osteogenesis, impairs skeletal structure, and impedes anabolic responses to mechanical loading. While the functions of VSCCs in osteoclasts is less clear, VSCCs have distinct but complementary functions in osteoblasts and osteocytes. This review details the structure, function, and nomenclature of VSCCs, followed by a comprehensive description of the known functions of VSCCs in bone cells and their regulation of bone development, bone formation, and mechanotransduction.
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    Soft Tissue Manipulation May Attenuate Inflammation, Modulate Pain, and Improve Gait in Conscious Rodents With Induced Low Back Pain
    (Oxford University Press, 2021) Loghmani, M. Terry; Tobin, Carolyn; Quigley, Colleen; Fennimore, Alanna; Physical Therapy, School of Health and Human Sciences
    Introduction: Low back pain (LBP) is common in warfighters. Noninvasive interventions are necessary to expedite return-to-function. Soft tissue manipulation, for example, massage, is a method used to treat LBP. Instrument-assisted soft tissue manipulation (IASTM) uses a rigid device to mobilize the tissue. This study explored the effects of IASTM on pain, function, and biomarkers. Methods: Sprague-Dawley rats (n = 44) were randomized to groups (n = 6/grp): (A) cage control; (B) 3 days (3d) postinjury (inj), untreated; (C) 3d inj, < 30-minute post-IASTM treatment; (D) 3d inj, 2 hours (2h) post-IASTM; (E) 14 days (14d) inj, untreated; (F) 14d inj, < 30-minute post-IASTM; and (G) 14d inj, 2h post-IASTM. Researchers induced unilateral LBP in Sprague-Dawley rats using complete Freund's adjuvant injection. Conscious rodents received IASTM for 5 min/session once at 3 days or 3×/week × 2weeks (6× total) over 14 days. Biomarker plasma levels were determined in all groups, while behavioral outcomes were assessed in two groups, D and G, at three time points: before injury, pre-, and post-IASTM treatment. Circulating mesenchymal stem cell levels were assessed using flow cytometry and cytokine plasma levels assayed. Results: The back pressure pain threshold (PPT) lowered bilaterally at 3 days postinjury (P < .05), suggesting increased pain sensitivity. IASTM treatment lowered PPT more on the injured side (15.8%; P < 0.05). At 14 days, back PPT remained lower but similar side to side. At 3 days, paw PPT increased 34.6% in the contralateral rear limb following treatment (P < .01). Grip strength did not vary significantly. Gait coupling patterns improved significantly (P < .05). Circulating mesenchymal stem cell levels altered significantly postinjury but not with treatment. Neuropeptide Y plasma levels increased significantly at 3 days, 2h post-IASTM (53.2%) (P < .05). Interleukin-6 and tumor necrosis factor-alpha did not vary significantly. At 14 days, regulated on activation, normal T cell expressed and secreted decreased significantly <30-minute post-IASTM (96.1%, P < .002), while IL-10 trended upward at 2h (53.1%; P = .86). Conclusions: LBP increased pain sensitivity and diminished function. IASTM treatment increased pain sensitization acutely in the back but significantly reduced pain sensitivity in the contralateral rear paw. Findings suggest IASTM may positively influence pain modulation and inflammation while improving gait patterns. Soft tissue manipulation may be beneficial as a conservative treatment option for LBP.
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    Generation of two multipotent mesenchymal progenitor cell lines capable of osteogenic, mature osteocyte, adipogenic, and chondrogenic differentiation
    (Springer Nature, 2021-11-19) Prideaux, Matthew; Wright, Christian S.; Noonan, Megan L.; Yi, Xin; Clinkenbeard, Erica L.; Mevel, Elsa; Wheeler, Jonathan A.; Byers, Sharon; Wijenayaka, Asiri R.; Gronthos, Stan; Sankar, Uma; White, Kenneth E.; Atkins, Gerald J.; Thompson, William R.; Physical Therapy, School of Health and Human Sciences
    Mesenchymal progenitors differentiate into several tissues including bone, cartilage, and adipose. Targeting these cells in vivo is challenging, making mesenchymal progenitor cell lines valuable tools to study tissue development. Mesenchymal stem cells (MSCs) can be isolated from humans and animals; however, obtaining homogenous, responsive cells in a reproducible fashion is challenging. As such, we developed two mesenchymal progenitor cell (MPC) lines, MPC1 and MPC2, generated from bone marrow of male C57BL/6 mice. These cells were immortalized using the temperature sensitive large T-antigen, allowing for thermal control of proliferation and differentiation. Both MPC1 and MPC2 cells are capable of osteogenic, adipogenic, and chondrogenic differentiation. Under osteogenic conditions, both lines formed mineralized nodules, and stained for alizarin red and alkaline phosphatase, while expressing osteogenic genes including Sost, Fgf23, and Dmp1. Sost and Dmp1 mRNA levels were drastically reduced with addition of parathyroid hormone, thus recapitulating in vivo responses. MPC cells secreted intact (iFGF23) and C-terminal (cFGF23) forms of the endocrine hormone FGF23, which was upregulated by 1,25 dihydroxy vitamin D (1,25D). Both lines also rapidly entered the adipogenic lineage, expressing adipose markers after 4 days in adipogenic media. MPC cells were also capable of chondrogenic differentiation, displaying increased expression of cartilaginous genes including aggrecan, Sox9, and Comp. With the ability to differentiate into multiple mesenchymal lineages and mimic in vivo responses of key regulatory genes/proteins, MPC cells are a valuable model to study factors that regulate mesenchymal lineage allocation as well as the mechanisms that dictate transcription, protein modification, and secretion of these factors.
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    Effect of fatigue loading and rest on impact strength of rat ulna
    (Elsevier, 2021-06) Yan, Chenxi; Song, Hyunggwi; Pfister, Jennifer; Andersen, Thomas L.; Warden, Stuart J.; Bhargava, Rohit; Kersh, Mariana E.; Physical Therapy, School of Health and Human Sciences
    Stress fracture is a common injury among athletes and military personnel and is associated with fatigue-initiated damage and impact loading. The recovery of bending strength has been shown to be a function of the rest days allowed after fatigue loading in rodents and the aim of this study was to investigate if similar results would occur under impact conditions. In this study, cyclic axial compression load was applied in vivo on the right forelimbs while left forelimbs served as controls. Two rest groups were used: one day of rest and seven days of rest. Afterwards, all ulnae were scanned using micro-Computed Tomography followed by impact testing. The micro-CT scan confirmed the formation of woven bone on loaded ulnae after seven days rest. The peak impact force was 37.5% higher in the control (mean = 174.96 ± 33.25 N) specimens compared to the loaded bones (mean = 130.34 ± 22.37 N). Fourier-transformed infrared spectroscopy analyses suggested no significant change of chemical composition in the cortical region between the loaded and control ulnae, but woven bone region had lower carbonate and amide I content than contralateral controls (p < 0.05). We find that cyclic fatigue loading had a negative effect on bone’s impact response. Bones that experienced fatigue loading became less stiff, weaker, and more prone to fracture when subjected to impact. The formation of woven bone after seven days of rest did not restore the stiffness upon impact and confirm that rest time is crucial to the recovery of fatigue damage.
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    Role of Bradykinin Type 2 Receptors in Human Sweat Secretion: Translational Evidence Does Not Support a Functional Relationship
    (Karger, 2021-04) Wilson, Thad E.; Narra, Seetharam; Metzler-Wilson, Kristen; Schneider, Artur; Bullens, Kelsey A.; Holt, Ian S.; Physical Therapy, School of Health and Human Sciences
    Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46–48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.