Vonda J. Wright

Synergistic enhancement of bone formation and healing by stem cell–expressed VEGF and bone morphogenetic protein-4

We investigated the interaction between angiogenic and osteogenic factors in bone formation and bone healing with ex vivo gene therapy using muscle-derived stem cells genetically engineered to express human bone morphogenetic protein-4 (BMP4), VEGF, or VEGF-specific antagonist (soluble Flt1). Our results show that although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation. These early effects, coupled with accelerated cartilage resorption, eventually led to a significant enhancement of bone formation and bone healing. The beneficial effect of VEGF on bone healing elicited by BMP4 depends critically on the ratio of VEGF to BMP4, with an improper ratio leading to detrimental effects on bone healing. Finally, we show that soluble Flt1 inhibits bone formation elicited by BMP4. Thus, VEGF plays an important role in bone formation elicited by BMP4, and it can significantly enhance BMP4-elicited bone formation and regeneration through multiple mechanisms. This study has important implications for the formulation of new strategies to improve bone healing through increasing mesenchymal stem cell recruitment and survival, in combination with muscle-derived stem cell-based gene therapy.

Biologic approaches to enhance rotator cuff healing after injury.

BACKGROUND Despite the advances in surgical procedures to repair the rotator cuff, there is a high incidence of failure. Biologic approaches, such as growth factor delivery and stem cell and gene therapy, are potential targets for optimization to improve the outcome of rotator cuff therapies and reduce rates of reinjury. This article outlines the current evidence for growth factor and stem cell therapy in tendon healing and the augmentation of rotator cuff repair. METHODS Literature on the PubMed-National Center for Biotechnology Information database was searched using the keywords growth factor, factor, gene therapy, stem cell, mesenchymal, or bone marrow in combination with rotator cuff, supraspinatus, or infraspinatus. Articles that studied growth factors or stem cells alone in rotator cuff repair were selected. Only 3 records showed use of stem cells in rotator cuff repair; thus, we expanded our search to include selected studies on stem cells and Achilles or patellar tendon repairs. Bibliographies and proceedings of meetings were searched to include additional applicable studies. We also included hitherto unpublished data by our group on the use of stem cell transplantation for rotator cuff therapy. RESULTS More than 70 articles are summarized, with focus on recent original research papers and significant reviews that summarized earlier records. CONCLUSIONS Use of growth factors, stem cell therapy, and other tissue-engineering means serve to augment classical surgical rotator cuff repair procedures. The combination of stem cells and growth factors resulted in enhanced repair that emulated uninjured tissue, but the literature search reflected paucity of research in this field. Preclinical evidence from gene therapy and stem cell studies can be used as a start to move therapy from the experimental phase to clinical translation in patients.

Age-Related Rates of Decline in Performance Among Elite Senior Athletes

Background Age-related disability and lost independence currently plague one third of older Americans. Many causes of disability, lost muscle mass and bone mineral density, are modifiable with exercise. Most exemplary of successful aging are the Senior Olympians; this group of vital athletes exhibit persistently high levels of functional capacity. Purpose This study describes demographic data, injury characteristics and the effect of aging on physical performance in senior athletes to identify key time points for intervention to address declining performance. Study Design Cross-sectional study; Level of evidence, 4. Methods Senior Olympians (>50 years) participating in the 2001 National Senior Olympic Games were surveyed for demographic and health characteristics. Age-related changes in physical performance were determined from mean winning performance times in track and field events. These were plotted against age and task for men and women. Analysis of variance and intergroup significance were analyzed using the Tukey procedure. Percentage performance change across events was compared. The 2001 National Senior Olympic Games results were compared with American track and field record holders. Results Senior athletes’ performance declined (male and female) approximately 3.4% per year over 35 years of competition—slowly from age 50 to 75 years and dramatically after age 75 years. Men showed no difference in decline of sprint and endurance events, whereas the decline in the sprint was greater than in endurance for women, especially after the age of 75 years. Conclusion Even the healthiest examples of musculoskeletal aging experience significant performance declines around age 75 years. This may be a key time point for preventive intervention.

Biological approaches to improve skeletal muscle healing after injury and disease

Skeletal muscle injury and repair are complex processes, including well-coordinated steps of degeneration, inflammation, regeneration, and fibrosis. We have reviewed the recent literature including studies by our group that describe how to modulate the processes of skeletal muscle repair and regeneration. Antiinflammatory drugs that target cyclooxygenase-2 were found to hamper the skeletal muscle repair process. Muscle regeneration phase can be aided by growth factors, including insulin-like growth factor-1 and nerve growth factor, but these factors are typically short-lived, and thus more effective methods of delivery are needed. Skeletal muscle damage caused by traumatic injury or genetic diseases can benefit from cell therapy; however, the majority of transplanted muscle cells (myoblasts) are unable to survive the immune response and hypoxic conditions. Our group has isolated neonatal skeletal muscle derived stem cells (MDSCs) that appear to repair muscle tissue in a more effective manner than myoblasts, most likely due to their better resistance to oxidative stress. Enhancing antioxidant levels of MDSCs led to improved regenerative potential. It is becoming increasingly clear that stem cells tissue repair by direct differentiation and paracrine effects leading to neovascularization of injured site and chemoattraction of host cells. The factors invoked in paracrine action are still under investigation. Our group has found that angiotensin II receptor blocker (losartan) significantly reduces fibrotic tissue formation and improves repair of murine injured muscle. Based on these data, we have conducted a case study on two hamstring injury patients and found that losartan treatment was well tolerated and possibly improved recovery time. We believe this medication holds great promise to optimize muscle repair in humans.

Model-Based Tracking of the Hip: Implications for Novel Analyses of Hip Pathology

This study investigated the efficacy of a combined high-speed, biplane radiography and model-based tracking technique to study hip joint kinematics and arthrokinematics. Comparing model-based tracking to the gold standard of radiostereometric analysis using implanted metal beads, joint translation was measured with a bias of 0.2 mm and a precision of 0.3 mm, whereas joint rotation was measured with a bias of 0.2° and a precision of 0.8°. A novel measure of hip arthrokinematics characterizing the region of closest contact in the anterosuperior acetabulum was measured with a bias of 0.9% and a precision of 2.5%. Model-based tracking of the hip thus provides the opportunity to noninvasively study hip pathologic conditions such as osteoarthritis and femoroacetabular impingement with great accuracy.

Participation in High-Impact Sports Predicts Bone Mineral Density in Senior Olympic Athletes

Background: Loss of bone mineral density (BMD) and resultant fractures increase with age in both sexes. Participation in resistance or high-impact sports is a known contributor to bone health in young athletes; however, little is known about the effect of participation in impact sports on bone density as people age. Hypothesis: To test the hypothesis that high-impact sport participation will predict BMD in senior athletes, this study evaluated 560 athletes during the 2005 National Senior Games (the Senior Olympics). Study Design: Cross-sectional methods. The athletes completed a detailed health history questionnaire and underwent calcaneal quantitative ultrasound to measure BMD. Athletes were classified as participating in high impact sports (basketball, road race [running], track and field, triathalon, and volleyball) or non-high-impact sports. Stepwise linear regression was used to determine the influence of high-impact sports on BMD. Results: On average, participants were 65.9 years old (range, 50 to 93). There were 298 women (53.2%) and 289 men (51.6%) who participated in high-impact sports. Average body mass index was 25.6 ± 3.9. The quantitative ultrasound-generated T scores, a quantitative measure of BMD, averaged 0.4 ± 1.3 and −0.1 ± 1.4 for the high-impact and non-high-impact groups, respectively. After age, sex, obesity, and use of osteoporosis medication were controlled, participation in high-impact sports was a significant predictor of BMD (R 2 change 3.2%, P < .001). Conclusions: This study represents the largest sample of BMD data in senior athletes to date. Senior participation in high-impact sports positively influenced bone health, even in the oldest athletes. Clinical Relevance: These data imply that high-impact exercise is a vital tool to maintain healthy BMD with active aging.

The Role of Mobility as a Protective Factor of Cognitive Functioning in Aging Adults A Review

Context: Over 33 chronic disease states and health disorders, including obesity and type 2 diabetes, are grouped into what is known as sedentary death syndrome. All these conditions are positively affected by 30 minutes of brisk exercise daily. In addition, only 30% of aging is based on genetics, with 70% on lifestyle. Therefore, a large majority of aging is controlled by individual health behaviors. Exercise is a powerful tool for healthy aging of the body and the mind. Courses of short- and long-term exercise provide benefits to musculoskeletal and cardiovascular health and can prevent age-related brain structural and functional losses. This review examines the evidence in support of mobility as an inexpensive and effective protective factor in maintaining brain health and preventing cognitive decline in aging adults. Evidence Acquisition: A PubMed search was performed for articles in English from 1990 to 2012. Reference lists were also reviewed and relevant articles obtained. Level of Evidence: Level 4. Results: Evidence suggests that maintaining a high level of cardiopulmonary fitness and mobility exhibits protective effects on structural changes that occur with aging in areas of the brain associated with memory, attention, and task completion. Chronic exercise is also associated with preservation of overall cognitive functioning and prevention of dementia. Conclusion: In combination with other preventative measures, physical mobility can assist in preventing or slowing cognitive decline in aging adults.

Chronic exercise preserves brain function in masters athletes when compared to sedentary counterparts

Abstract Objective: Exercise is beneficial for both the body and the mind, and it has been associated with protective neurocognitive effects, such as increased levels of brain-derived neurotrophic factor and neurogenesis. These effects are linked to the attenuation of age-related mental decline and the preservation of mental capacities in older, physically active adults. This study evaluated whether masters athletes, a highly active population, have better cognitive function compared to age-matched non-athletes based on the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) tool. Methods: Masters athletes and sedentary controls were recruited and screened for eligibility. All subjects were excluded if they had preexisting neurological diseases, psychiatric disorders, substance abuse disorders, learning disorders, and/or a history of traumatic brain injury, and in addition, control subjects were excluded if they performed >1 h/week of aerobic exercise. All participants completed a health and activity survey which includes the SF-12 and the ImPACT neurocognitive test which measures verbal and visual memory as well as reaction time. Differences between masters athletes and the control population were determined by ImPACT score composites. Results: 51 pairs of athletes and non-athletes were analyzed. Athletes had significantly higher verbal memory scores (85.9 ± 7.7 vs 79.9 ± 13.9, p = 0.01) and faster reaction times (0.71 ± 0.12 vs 0.76 ± 0.15 s, p = 0.04) on the ImPACT test. Athletes also scored significantly higher on the physical components summary score of the SF-12 (55.0 ± 3.3 vs 51.8 ± 6.7, p = 0.004). Conclusion: Masters athletes performed better on verbal memory and reaction time test, as well as on physical function as evaluated by the SF-12, compared to non-athlete controls. Chronic physical activity may preserve neurocognitive processes and increase physical health, which are protective factors for the negative effects of the aging process.

Bilateral sacroiliac joint dislocation without associated fracture or anterior pelvic ring injuries.

Summary: SI joint dislocations are serious injuries. They are often associated with posterior fractures or anterior ring disruptions. This case report documents the outcome of a patient with an uncommon injury involving bilateral SI joint dislocation without associated anterior pelvic injuries or posterior pelvic fracture.

A Review of Femoroacetabular Impingement and Hip Arthroscopy in the Athlete

Abstract Femoroacetabular impingement (FAI) is increasingly recognized as a pathological condition of the hip in athletes. Although it is not always symptomatic, the bone structure leading to FAI and its associated pathology can result in significant pain and performance decline in athletes. Recognition of athletes with symptomatic FAI is of the utmost importance, as prompt treatment is necessary in order to maintain desired sports activity levels and preserve joint function. This review explores the recent evidence on the evaluation, recognition, and treatment of femoroacetabular impingement, and discusses conservative management, postoperative rehabilitation, and treatment in the pediatric and master athlete populations.