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1.  Adiponectin Is a Candidate Biomarker of Lower Extremity Bone Density in Men With Chronic Spinal Cord Injury 
Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.
PMCID: PMC3979427  PMID: 23787489
2.  Spinal Cord Injury and Osteoporosis: Causes, Mechanisms, and Rehabilitation Strategies 
Spinal cord injury (SCI) has a huge impact on the individual, society and the economy. Though advances in acute care resulted in greatly reduced co-morbidities, there has been much less progress preventing long-term sequelae of SCI. Among the long-term consequences of SCI is bone loss (osteoporosis) due to the mechanical unloading of the paralyzed limbs and vascular dysfunction below the level of injury. Though osteoporosis may be partially prevented via pharmacologic interventions during the acute post-injury phase, there are no clinical guidelines to treat osteoporosis during the chronic phase. Thus there is need for scientific advances to improve the rehabilitative approaches to SCI-related osteoporosis. Recent advances in application of a new technology, functional electrical stimulation, provide a new and exciting opportunity to improve bone metabolism and to provide mechanical strain to the paralyzed lower limbs sufficient to stimulate new bone formation in individuals with SCI. The purpose of this minireview is to delineate our current understanding of SCI-related osteoporosis and to highlight recent literature towards its prevention and treatment.
PMCID: PMC4238383  PMID: 25419534
Spinal cord injury; SCI-related osteoporosis; Chronic post-injury phase
3.  Snx10: a newly identified locus associated with human osteopetrosis 
IBMS boneKEy  2013;2013(10):421.
PMCID: PMC4237201  PMID: 25419438
4.  Neurotoxic or Neuroprotective? Current Controversies in SCI-Induced Autoimmunity 
Current physical medicine and rehabilitation reports  2013;1(3):10.1007/s40141-013-0021-2.
Controversy exists regarding the autoimmune response that has been observed following traumatic spinal cord injury (SCI). It is not clear if this represents a protective response by the immune system to prevent further tissue damage, a pathological reaction of the immune system to central nervous system antigens released by the injury, or a combination of both. Experimental evidence indicates that B cells produce auto-antibodies following SCI and that the presence of self-reactive antibodies is associated with tissue damage. Conversely, other studies suggest T cell activity at the site of the injury promotes tissue regeneration. Vaccination with dendritic cells exposed to central nervous system (CNS) antigens dramatically improves recovery of motor function in spinal cord injured rats. Further research is required to determine the nature of post-SCI B cell and T cell responses and to establish efficacy of dendritic cell vaccination therapy in clinical studies. This information is critical for the development of therapies to either suppress or promote immune responses following neurotrauma to improve neurological outcomes.
PMCID: PMC3883451  PMID: 24416711
Spinal Cord Injury; B cell; T cell; Dendritic cell; Autoimmunity; Rehabilitation
5.  B-Cell Maturation Antigen, A Proliferation-Inducing Ligand, and B-Cell Activating Factor Are Candidate Mediators of Spinal Cord Injury-Induced Autoimmunity 
Journal of Neurotrauma  2013;30(6):434-440.
Autoimmunity is thought to contribute to poor neurological outcomes after spinal cord injury (SCI). There are few mechanism-based therapies, however, designed to reduce tissue damage and neurotoxicity after SCI because the molecular and cellular bases for SCI-induced autoimmunity are not completely understood. Recent groundbreaking studies in rodents indicate that B cells are responsible for SCI-induced autoimmunity. This novel paradigm, if confirmed in humans, could aid in the design of neuroprotective immunotherapies. The aim of this study was to investigate the molecular signaling pathways and mechanisms by which autoimmunity is induced after SCI, with the goal of identifying potential targets in therapies designed to reduce tissue damage and inflammation in the chronic phase of SCI. To that end, we performed an exploratory microarray analysis of peripheral blood mononuclear cells to identify differentially expressed genes in chronic SCI. We identified a gene network associated with lymphoid tissue structure and development that was composed of 29 distinct molecules and five protein complexes, including two cytokines, a proliferation-inducing ligand (APRIL) and B-cell–activating factor (BAFF), and one receptor, B-cell maturation antigen (BMCA) involved in B cell development, proliferation, activation, and survival. Real-time polymerase chain reaction analysis from ribonucleic acid samples confirmed upregulation of these three genes in SCI. To our knowledge, this is the first report that peripheral blood mononuclear cells produce increased levels of BAFF and APRIL in chronic SCI. This finding provides evidence of systemic regulation of SCI-autoimmunity via APRIL and BAFF mediated activation of B cells through BMCA and points toward these molecules as potential targets of therapies designed to reduce neuroinflammation after SCI.
PMCID: PMC3627405  PMID: 23088438
autoimmunity; B cell; rehabilitation; spinal cord injury
6.  Spinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies 
Current osteoporosis reports  2012;10(4):278-285.
Spinal cord injury causes rapid, severe osteoporosis with increased fracture risk. Mechanical unloading after paralysis results in increased osteocyte expression of sclerostin, suppressed bone formation, and indirect stimulation of bone resorption. At this time there are no clinical guidelines to prevent bone loss after SCI and fractures are common. More research is required to define the pathophysiology and epidemiology of SCI-induced osteoporosis. This review summarizes emerging therapeutics including anti-sclerostin antibodies, mechanical loading of the lower extremity with electrical stimulation, and mechanical stimulation via vibration therapy.
PMCID: PMC3508135  PMID: 22983921
Osteoporosis; Sclerostin; Bone Mineral Density; Spinal Cord Injury; Mechanical unloading
7.  Concurrent muscle and bone deterioration in a murine model of cancer cachexia 
Physiological Reports  2013;1(6):e00144.
Cachexia is defined as an excessive, involuntary loss of fat and lean tissue. We tested the validity of the Lewis lung carcinoma (LLC) as a model of cancer cachexia and examined its effect on the two major lean tissue components, skeletal muscle and bone. LLC cells (0.75 × 106) were injected into the left thigh of C57BL/6 mice. Control mice received an equal volume injection of growth media. Tumors were observed in all LLC-injected animals 21 and 25 days post inoculation. LLC-injected animals showed significant reductions in fat and lean mass despite having the same average daily caloric intake as media-treated mice. Global bone mineral density (BMD) had fallen by 5% and 6% in the LLC animals at 21 and 25 days, respectively, compared to a BMD increase of 5% in the 25-day media-treated animals. Extensor digitorum longus (EDL) muscles (isolated from the noninjected hindlimb) showed earlier and quantitatively greater losses in mass, physiological cross-sectional area (pCSA), and tetanic force compared to soleus muscles from the same hindlimb. By the 25th day post-LLC inoculation, EDL force/pCSA was reduced by 19% versus media treatment. This loss in specific force was not trivial as it accounted for about one-third of the reduction in EDL absolute force at this time point. Muscle strips dissected from the diaphragm of LLC mice also exhibited significant reductions in force/pCSA at day 25. We conclude that LLC is a valid model of cachexia that induces rapid losses in global BMD and in limb and respiratory muscle function.
PMCID: PMC3871459  PMID: 24400146
Body composition; bone mineral density; muscle function; muscle strength
8.  Circulating sclerostin is elevated in short-term and reduced in long-term SCI 
Bone  2012;51(3):600-605.
Spinal cord injury (SCI) causes profound bone loss due to muscle paralysis resulting in the inability to walk. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. Although sclerostin inhibition has been proposed as a potential therapy for bone loss, it is not known if sclerostin levels vary with duration of SCI in humans. We analyzed circulating sclerostin in 155 men with varying degrees of SCI who were 1 year or more post-injury. We report that sclerostin levels are greatest in subjects with short-term SCI (≤ 5 years post-injury) and decrease significantly over the first 5 years post-injury. There was no association between sclerostin and injury duration in subjects with long-term SCI (> 5 years post-injury). In subjects with long-term SCI, sclerostin levels were positively associated with lower extremity bone density and bone mineral content. These data suggest that sclerostin levels in SCI are initially increased after SCI in response to mechanical unloading. This response is time-limited and as bone loss progresses, circulating sclerostin is lowest in subjects with severe osteoporosis. These findings support a dual role for sclerostin after SCI: a therapeutic target in acute SCI, and a biomarker of osteoporosis severity in chronic SCI.
PMCID: PMC3412894  PMID: 22575440
Osteoporosis; Sclerostin; Spinal Cord Injury; Rehabilitation Medicine
9.  Association between Sclerostin and Bone Density in Chronic SCI 
Spinal cord injury (SCI) results in profound bone loss due to muscle paralysis and the inability to ambulate. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. These studies suggest that complete spinal cord injury, a condition resulting in mechanical unloading of the paralyzed lower extremities, will be associated with high sclerostin levels. We assessed the relationship between circulating sclerostin and bone density in 39 subjects with chronic SCI and 10 without SCI. We found that greater total limb bone mineral content was significantly associated with greater circulating levels of sclerostin. Sclerostin levels were reduced, not elevated, in subjects with SCI who use a wheelchair compared to those with SCI who walk regularly. Similarly, sclerostin levels were lower in subjects with SCI who use a wheelchair compared to persons without SCI who walk regularly. These findings suggest that circulating sclerostin is a biomarker of osteoporosis severity, not a mediator of ongoing bone loss, in long-term, chronic paraplegia. This is in contrast to the acute sclerostin-mediated bone loss demonstrated in animal models of mechanical unloading where high sclerostin levels suppress bone formation. As these data indicate important differences in the relationship between mechanical unloading, sclerostin, and bone in chronic SCI compared to short-term rodent models, it is likely that sclerostin is not a good therapeutic target to treat chronic SCI-induced osteoporosis.
PMCID: PMC3288145  PMID: 22006831
Bone Fracture; Osteoporosis; Sclerostin; Spinal Cord Injury; Rehabilitation Medicine
10.  Hybrid Matrix Grafts to Favor Tissue Regeneration in Rabbit Femur Bone Lesions 
At present, typical approaches employed to repair fractures and other bone lesions tend to use matrix grafts to promote tissue regeneration. These grafts act as templates, which promote cellular adhesion, growth and proliferation, osteoconduction, and even osteoinduction, which commonly results in de novo osteogenesis. The present work aimed to study the bone-repairing ability of hybrid matrixes (HM) prepared with polyvinyl alcohol (PVA) and bioactive glass in an experimental rabbit model. The HM were prepared by combining 30% bioactive glass (nominal composition of 58% SiO2 -33 % CaO - 9% P2O5) and 70% PVA. New Zealand rabbits were randomly divided into the control group (C group) and two groups with bone lesions, in which one received a matrix implant HM (Implant group), while the other did not (no Implant group). Clinical monitoring showed no altered parameters from either the Implant or the no Implant groups as compared to the control group, for the variables of diet grades, day and night temperatures and hemograms. In the Implant group, radiologic and tomographic studies showed implanted areas with clean edges in femoral non-articular direction, and radio-dense images that suggest incipient integration. Minimum signs of phlogosis could be observed, whereas no signs of rejection at this imaging level could be identified. Histological analysis showed evidence of osteo-integration, with the formation of a trabecular bone within the implant. Together, these results show that implants of hybrid matrixes of bioactive glass are capable of promoting bone regeneration.
PMCID: PMC3406269  PMID: 22848334
Bone regeneration; hybrid matrix; bioactive glass; polyvinyl alcohol; femur bone lesion.
11.  Severe Spinal Cord Injury Causes Immediate Multi-cellular Dysfunction at the Chondro-Osseous Junction 
Translational stroke research  2011;2(4):643-650.
Spinal cord injury is associated with rapid bone loss and arrested long bone growth due to mechanisms that are poorly understood. In this study, we sought to determine the effects of severe T10 contusion spinal cord injury on the sublesional bone microenvironment in adolescent rats. A severe lower thoracic (vertebral T10) spinal cord injury was generated by weight drop (10 g×50 mm). Severely injured and body weight-matched uninjured male Sprague–Dawley rats were studied. At 3 and 5 days post-injury, we performed histological analysis of the distal femoral metaphysis, TUNEL assay, immunohistochemistry, real-time PCR, and western blot analysis compared to uninjured controls. We observed severe hindlimb functional deficits typical of this model. We detected uncoupled remodeling with increased osteoclast activity in the absence of osteoblast activity. We detected osteoblast, osteocyte, and chondrocyte apoptosis with suppressed osteoblast and chondrocyte proliferation and growth plate arrest due to spinal cord injury. We also detected altered gene expression in both whole bone extracts and bone marrow monocytes following spinal cord injury. We conclude that spinal cord injury results in altered gene expression of key regulators of osteoblast and chondrocyte activity. This leads to premature cellular apoptosis, suppressed cellular proliferation, growth plate arrest, and uncoupled bone remodeling in sublesional bone with unopposed osteoclastic resorption.
PMCID: PMC3285243  PMID: 22368723
Rehabilitation medicine; Spinal cord injury; Osteoporosis; Osteoblast; Chondrocyte
12.  Mutational Analysis of NHAoc/NHA2 in Saccharomyces cerevisiae 
Biochimica et biophysica acta  2010;1800(12):1241-1247.
NHAoc/NHA2 is highly and selectively expressed in osteoclasts and plays a role(s) in normal osteoclast differentiation, apoptosis and bone resorptive function in vitro. Extensive mutational analysis of a bacterial homologue, NhaA, has revealed a number of amino acid residues essential for its activity. Some of these residues are evolutionarily conserved and have been shown to be essential not only for activity of NhaA in bacteria, but also of NHAoc/NHA2 in eukaryotes.
The salt-sensitive Saccharomyces cerevisiae strain BW31a was used for heterologous expression of mutants of NHAoc/NHA2. Membrane expression of NHAoc/NHA2 was confirmed by confocal microscopy. Intracellular concentration of Na+ (a measure of Na+ antiporter activity) was estimated by atomic absorption spectroscopy. The growth phenotypes of cells expressing NHAoc/NHA2 mutants were studied on YNB agar supplemented with NaCl and by growth curves in YNB broth.
Mutations in amino acid residues V161 and F357 reduced the ability of transfected BW31a cells to remove intracellular sodium and to grow in NaCl-containing medium. Yeast expressing the double mutant F357 F437 can not grow in 0.4 M NaCl, suggesting that these residues are also essential for antiporter activity.
Evolutionarily conserved amino acids are required for full antiporter function.
General Significance
Mutations in these amino acid residues may impact NHAoc activity and therefore osteoclast function in vitro and in vivo.
PMCID: PMC2967667  PMID: 20713131
13.  PAMM: A Redox Regulatory Protein That Modulates Osteoclast Differentiation 
Antioxidants & Redox Signaling  2010;13(1):27-37.
The central role of reactive oxygen species (ROS) in osteoclast differentiation and in bone homeostasis prompted us to characterize the redox regulatory system of osteoclasts. In this report, we describe the expression and functional characterization of PAMM, a CXXC motif–containing peroxiredoxin 2–like protein expressed in bone marrow monocytes on stimulation with M-CSF and RANKL. Expression of wild-type (but not C to G mutants of the CXXC domain) PAMM in HEK293 cells results in an increased GSH/GSSG ratio, indicating a shift toward a more reduced environment. Expression of PAMM in RAW264.7 monocytes protected cells from hydrogen peroxide–induced oxidative stress, indicating that PAMM regulates cellular redox status. RANKL stimulation of RAW 264.7 cells caused a decrease in the GSH/GSSG ratio (reflecting a complementary increase in ROS). In addition, RANKL-induced osteoclast formation requires phosphorylation and translocation of NF-κB and c-Jun. In stably transfected RAW 264.7 cells, PAMM overexpression prevented the reduction of GSH/GSSG induced by RANKL. Concurrently, PAMM expression completely abolished RANKL-induced p100 NF-κB and c-Jun activation, as well as osteoclast formation. We conclude that PAMM is a redox regulatory protein that modulates osteoclast differentiation in vitro. PAMM expression may affect bone resorption in vivo and help to maintain bone mass. Antioxid. Redox Signal. 13, 27–37.
PMCID: PMC2877117  PMID: 19951071
14.  18beta-Glycyrrhetinic Acid Inhibits Periodontitis Via Glucocorticoid-Independent NF–κB Inactivation In IL-10 Deficient Mice 
Journal of periodontal research  2010;45(6):757-763.
Background and objective
18beta-glycyrrhetinic acid (GA) is a natural anti-inflammatory compound derived from licorice root extract (Glycyrrhiza glabra). The effect of GA on experimental periodontitis and its mechanism of action were determined in the present study.
Periodontitis was induced by oral infection with Porphyromonas gingivalis W83 in IL-10 deficient mice. The effect of GA, which was delivered by subcutaneous injections in either prophylactic or therapeutic regimens, on alveolar bone loss and gingival gene expressions was determined on day 42 after initial infection. The effect of GA on LPS-stimulated macrophages, T cell proliferation, and osteoclastogenesis was also examined in vitro.
GA administered either prophylactically or therapeutically dramatically reduced infection-induced bone loss in IL-10 deficient mice, which are highly disease-susceptible. Although GA has been reported to exert its anti-inflammatory activity via down-regulation of 11-beta hydroxysteroid dehydrogenase-2 (HSD2), which converts active glucocorticoids (GC) to their inactive forms, GA did not reduce HSD2 gene expression in gingival tissue. Rather, under GC-free conditions, GA potently inhibited LPS-stimulated proinflammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are NF–κB-dependent. GA furthermore suppressed LPS- and RANKL-stimulated phosphorylation of NF–κB p105 in vitro.
These findings indicate that GA inhibits periodontitis by inactivation of NF–κB in an IL-10 and GC-independent fashion.
PMCID: PMC3075584  PMID: 20682015
18beta-glycyrrhetinic acid; periodontal disease; NF–κB; IL-10 deficient mouse
15.  Endodontic antimicrobial photodynamic therapy: Safety assessment in mammalian cell cultures 
Journal of endodontics  2009;35(11):1567-1572.
To assess the in vitro synergistic effect of methylene blue (MB) and red light on human gingival fibroblasts and osteoblasts with parameters similar to those that may be applied in a clinical setting for endodontic disinfection.
Materials and Methods
Both cell types were sensitized with 50 μg/ml MB followed by exposure to red light at 665 nm for 5 minutes with an irradiance of 10, 20 and 40 mW/cm2. Following photodynamic therapy (PDT), cell viability and mitochondrial activity were evaluated by the neutral red and MTT assay, respectively. Assessment of PDT-induced apoptosis was investigated by western blot analysis using cleaved poly(ADP-ribose) polymerase - specific antibodies.
Light at 20 and 40 mW/cm2 with MB had modest effects at 24 hours on osteoblasts in both assays, whereas sodium hypochlorite (NaOCl) completely eliminated cells. Western blot analysis revealed no signs of apoptosis in either cell type.
The data suggest that there is a safe therapeutic window whereby PDT can inactivate endodontic pathogens without affecting host cell viability.
PMCID: PMC2776084  PMID: 19840649
endodontic disinfection; photodynamic therapy; safety; methylene blue; mammalian cells
16.  VA-Based Survey of Osteoporosis Management in Spinal Cord Injury 
Although osteoporosis is common following spinal cord injury (SCI), no guidelines exist for its treatment, diagnosis, or prevention. The authors hypothesized that wide variations in diagnosis and treatment practices result from the absence of guidelines. This study sought to characterize the diagnosis and management practices within the VA health care system for osteoporosis following SCI.
Online survey regarding osteoporosis management in SCI composed of 27 questions designed to gather information on responder demographics, osteoporosis diagnostics, and treatment options.
VA health care system.
VHA National SCI Staff Physicians and VHA National SCI Nurses (total n = 450) were sent an email with an invitation to participate.
Not applicable.
Main Outcome Measures
Practice patterns were assessed, including factors associated with ordering a clinical workup and prescribing osteoporosis treatment.
The response rate was 28%. Ninety-two prescribing practitioners (physicians, nurse practitioners, and physician assistants) were included in the analysis. Of these respondents, 50 (54%) prescribe medications for SCI-induced bone loss; 39 (42%) prescribe bisphosphonates and 46 (50%) prescribe vitamin D. There were 54 (59%) respondents who routinely order diagnostic tests, including dual energy x-ray absorptiometry scans in 50 (54%). Variations in practice were not explained by age, gender, or years practicing SCI medicine. Many respondents (23%) reported barriers to osteoporosis testing including lack of scanning protocols, cost, wheelchair inaccessibility of scanning facilities, and lack of effective treatment guidelines once osteoporosis is diagnosed.
Despite an absence of screening and treatment guidelines, more than half of all respondents are actively diagnosing and treating osteoporosis with bisphosphonates within the VA health care setting. These data suggest that evidence-based practice guidelines are necessary to reduce practice variations and improve clinical care for this population.
PMCID: PMC2791704  PMID: 19627901
17.  Dual Energy X-Ray Absorptiometry of the Distal Femur May Be More Reliable than the Proximal Tibia in Spinal Cord Injury 
Although spinal cord injury frequently results in low impact fractures at the distal femur and proximal tibia, there are no standard clinical protocols for assessing bone mineral density at these sites. We evaluated the precision of dual energy x-ray absorptiometry scanning at two skeletal sites at the knee (proximal femur and distal tibia) in individuals with spinal cord injury.
VA Medical Center.
20 subjects with chronic SCI.
Not Applicable.
Main Outcome Measures
Precision as determined by root mean square coefficient of variation (RMS-CV) and root mean standard deviation (RMS-SD).
At the distal femur the root RMS-CV was 3.01% and the RMS-SD was 0.025 g/cm2. At the proximal tibia the RMS-CV was 5.91% and the RMS-SD was 0.030 g/cm2.
Precision at the distal femur is greater than the proximal tibia and we recommend it as the preferred site for the longitudinal assessment of bone mineral density at the knee in chronic spinal cord injury.
PMCID: PMC2677191  PMID: 19406303
Spinal Cord Injury; Osteoporosis; Bone Mineral Density; Precision

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