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OBJECTIVES Patients with microscopic colitis may have subtle macroscopic findings on colonoscopy such as erythema, edema, or altered vascular pattern; however, radiographic abnormalities on cross-sectional imaging have not been investigated. We aimed at identifying the abdominopelvic radiographic abnormalities in patients with microscopic colitis, as well as possible correlation with endoscopic findings and the need for extended duration of treatment. MATERIALS AND METHODS This was a retrospective study of patients with biopsy-proven microscopic colitis at two tertiary centers between 1 January 2010 and 30 April 2020. Patients underwent computed tomography scan or magnetic resonance imaging within 30 days of a diagnostic flexible sigmoidoscopy or colonoscopy. Patients with colon ischemia and other causes of colitis were excluded. Radiographic abnormalities from imaging reports included bowel wall thickening, mucosal hyperenhancement and mesenteric fat stranding. Univariate and multivariable logistic regression models were used to identify predictors of radiographic abnormalities. RESULTS 498 patients with microscopic colitis underwent abdominopelvic cross-sectional imaging within 30 days of flexible sigmoidoscopy/colonoscopy. Lymphocytic colitis was diagnosed in 54.6% of patients, and collagenous colitis in 45.4%. Endoscopic and radiographic abnormalities were identified in 16.1% and 12.4% of patients, respectively. Radiographic abnormalities were associated with the need for budesonide therapy (p = .029) and budesonide therapy long-term (p = .0028). Budesonide therapy long-term (p = .047) was associated with radiographic abnormalities in multivariate analysis. CONCLUSIONS Radiographic abnormalities may be present on abdominopelvic cross-sectional imaging in a minority of patients with biopsy-proven microscopic colitis, suggesting cross-sectional imaging has low clinical value in the evaluation and treatment of this disease.

Sinus disease is commonly encountered, especially in the acute care setting. Imaging can support a diagnosis of sinusitis, help identify an etiology, and delineate intracranial and extracranial complications. Suspicion of complicated rhinosinusitis is an indication for contrast-enhanced computed tomography or magnetic resonance imaging. It is important for radiologists to be familiar with patient risk factors that predispose to uncommon but aggressive forms of sinus disease such as invasive fungal sinusitis. Lastly, many conditions, ranging from benign to malignant, can mimic rhinosinusitis clinically and on imaging. Radiologists can help by recognizing these entities and facilitating appropriate referral and follow-up. This article reviews the breadth of sinus disease commonly encountered in the emergency setting, potential complications, and mimics.

Smooth muscle conditions of the chest have diverse clinical and imaging manifestations and may involve nearly every thoracic structure. Differentiation among these conditions requires the integration of clinical, radiologic, and histopathologic data. Histologic examination in conjunction with immunohistochemistry is essential for differentiation from other spindle cell neoplastic mimics. Familiarity with these entities will ensure the inclusion of smooth muscle conditions in the differential diagnosis of thoracic soft tissue lesions and potentially guide the clinician in appropriate management. We review the clinical, imaging, and histopathologic features of thoracic smooth muscle-related conditions organized by the anatomic structures affected.

OBJECTIVEExisting literature supports benefits of early tracheostomy and percutaneous endoscopic gastrostomy (PEG) in certain patient populations. The aim of this study was to review tracheostomy and PEG placement data in patients with hemorrhagic stroke in order to identify factors associated with earlier placement and to evaluate outcomes.METHODSThe authors performed a retrospective review of consecutive patients treated for hemorrhagic stroke between June 1, 2011, and June 1, 2015. Data were analyzed by logistic and multiple linear regression.RESULTSOf 240 patients diagnosed with hemorrhagic stroke, 31.25% underwent tracheostomy and 35.83% underwent PEG tube placement. Factors significantly associated with tracheostomy and PEG included the presence of pneumonia on admission and subarachnoid hemorrhage. Earlier tracheostomy was significantly associated with shorter ICU length of stay; earlier tracheostomy and PEG placement were associated with shorter overall hospitalization. Timing of tracheostomy and PEG was not significantly associated with patient survival or the incidence of complications in this population.CONCLUSIONSThis study identified patient risk factors associated with increased likelihood of tracheostomy and PEG in patients with hemorrhagic stroke who were critically ill. Additionally, we found that the timing of tracheostomy was associated with length of ICU stay and overall hospital stay, and that the timing of PEG was associated with overall length of hospitalization. Complication rates related to tracheostomy and PEG in this population were minimal. This retrospective data set supports some benefit to earlier tracheostomy and PEG placement in this population and justifies the need for further prospective study.

Introduction: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders that affects females of reproductive age. The characteristic features of PCOS individually have opposing effects on bone mineral density (BMD); however, their cumulative effect on BMD has not been clearly defined. Adolescence and young adulthood span a crucial period in achieving peak bone mass. Thus, a better understanding of the impact of PCOS on BMD in this age group is needed. Objectives: To determine whether BMD is different between young females with PCOS and controls and to identify factors that influence BMD in this population. Methods: Data from four cross-sectional studies with a total of 170 females aged 12–25 years with PCOS (n = 123) and controls (n = 47) with a wide range of BMIs (18.7–53.4 kg/m2) were analyzed. Participants had fasting glucose, insulin, and free and total testosterone concentrations measured. HOMA-IR was calculated. Whole-body BMD was assessed by dual-energy X-ray absorptiometry. Multiple regression analysis for predicting BMD included PCOS status, menstrual age, obesity, HOMA-IR, and free testosterone. Results: HOMA-IR and total and free testosterone were significantly higher in PCOS compared to controls but there was no difference in BMD z-score between PCOS (0.8 ± 1.0) and controls (0.6 ± 1.0) (p = 0.36). Obesity (p = 0.03) and HOMA-IR (p = 0.02) were associated with BMD z-score. Conclusions: Obesity status and insulin resistance, but not PCOS status, were each independently associated with BMD in adolescents and young women who spanned a wide range of BMIs.

OBJECTIVES: Burn patients have a highly variable length-of-stay (LOS) due to the complexity of the burn injury itself. The LOS for burn patients is estimated as one day per percent total body surface area (TBSA) burn. To focus care expectation and prognosis we aimed to identify key factors that contribute to prolonged LOS. METHODS: This was a retrospective cohort-study (2006–2016) in an adult burn-centre that included patients with ≥10% TBSA burn. Patients were stratified into expected-LOS (2days LOS/%TBSA). We assessed demographics, comorbidities, and in-hospital complications. Logistic regression and propensity matching was utilized. RESULTS: Of the 583 total patients, 477 had an expected-LOS whereas 106 a longer-than-expected-LOS. Non-modifiable factors such as age, 3(rd) degree TBSA%, inhalation injuries and comorbidities were greater in the exceeded LOS patients. Subsequent matched analysis revealed factors like number of procedures performed, days ventilated and in-hospital complications (bacteremia, pneumonia, sepsis, graft loss, and respiratory failure) were significantly increased in the longer-than-expected-LOS group. CONCLUSIONS: Progress has been made to update the conventional one day/%TBSA to better aid health care providers in giving appropriate outcomes for patients and their families and to supply intensive care units with valuable data to assess quality of care and to improve patient prognosis.

Sinus disease is commonly encountered, especially in the acute care setting. Imaging can support a diagnosis of sinusitis, help identify an etiology, and delineate intracranial and extracranial complications. Suspicion of complicated rhinosinusitis is an indication for contrast-enhanced computed tomography or magnetic resonance imaging. It is important for radiologists to be familiar with patient risk factors that predispose to uncommon but aggressive forms of sinus disease such as invasive fungal sinusitis. Lastly, many conditions, ranging from benign to malignant, can mimic rhinosinusitis clinically and on imaging. Radiologists can help by recognizing these entities and facilitating appropriate referral and follow-up. This article reviews the breadth of sinus disease commonly encountered in the emergency setting, potential complications, and mimics.

The most important determinant of survival post-burn injury is wound healing. For decades, allogeneic mesenchymal stem cells (MSCs) have been suggested as a potential treatment for severe burn injuries. This report describes a patient with a severe burn injury whose wounds did not heal with over 18 months of conventional burn care. When treated with allogeneic MSCs, wound healing accelerated with no adverse treatment complications. Wound sites showed no evidence of keloids or hypertrophic formation during a 6-year follow-up period. This therapeutic use of allogeneic MSCs for large non-healing burn wounds was deemed safe and effective and has great treatment potential.

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Purpose/Aim: The intervertebral disc (IVD) is composed of cell types whose subtle phenotypic differences allow for the formation of distinct tissues. The role of the nucleus pulposus (NP) in the initiation and progression of IVD degeneration is well established; however, the genes and pathways associated with NP degeneration are poorly characterized. Materials and Methods: Using a genetic strategy for IVD lineage-specific fluorescent reporter expression to isolate cells, gene expression and bioinformatic analysis was conducted on the murine NP at 2.5, 6, and 21 months-of-age and the annulus fibrosus (AF) at 2.5 and 6 months-of-age. A subset of differentially regulated genes was validated by qRT-PCR. Results: Transcriptome analysis identified distinct profiles of NP and AF gene expression that were remarkably consistent at 2.5 and 6 months-of-age. Prg4, Cilp, Ibsp and Comp were increased >50-fold in the AF relative to NP. The most highly enriched NP genes included Dsc3 and Cdh6, members of the cadherin superfamily, and microRNAs mir218-1 and mir490. Changes in the NP between 2.5 and 6 months-of-age were associated with up-regulation of molecular functions linked to laminin and Bmp receptor binding (including up-regulation of Bmp5 & 7), with the most up-regulated genes being Mir703, Shh, and Sfrp5. NP degeneration was associated with molecular functions linked to alpha-actinin binding (including up-regulation of Ttn & Myot) and cytoskeletal protein binding, with the overall most up-regulated genes being Rnu3a, Snora2b and Mir669h. Conclusions: This study provided insight into the phenotypes of NP and AF cells, and identified candidate pathways that may regulate degeneration.

Globally, obesity is on the rise with ~ 30% of the world’s population now obese, and childhood obesity is following similar trends. Childhood obesity has been associated with numerous chronic conditions, including musculoskeletal disorders. This review highlights the effects of childhood adiposity on bone density by way of analyzing clinical studies and further describing two severe skeletal conditions, slipped capital femoral epiphysis and Blount’s disease. The latter half of this review discusses bone remodeling and cell types that mediate bone growth and strength, including key growth factors and transcription factors that help orchestrate this complex pathology. In particular, the transcriptional factor peroxisome proliferator-activated receptor gamma (PPARγ) is examined as it is a master regulator of adipocyte differentiation in mesenchymal stem cells (MSCs) that can also influence osteoblast populations. Obese individuals are known to have higher levels of PPARγ expression which contributes to their increased adipocyte numbers and decreased bone density. Modulating PPAR*gamma* signaling can have significant effects on adipogenesis, thereby directing MSCs down the osteoblastogenesis pathway and in turn increasing bone mineral density. Lastly, we explore the potential of PPARγ as a druggable target to decrease adiposity, increase bone density, and be a treatment for children with obesity-induced bone fractures.

Objectives The purpose of this study was to determine whether having a previous diagnosis of multiple sclerosis (MS) changed acute care needs in burn-injured patients. Methods This was a retrospective case-control study that included adult (aged ≥18 years) patients with an acute burn injury. Control patients were matched with eleven patients with a history of MS at a 4:1 ratio. Outcomes included fluid resuscitation volumes, temperature, heart rate, mean arterial pressure, in-hospital complications, and hospital length of stay (LOS). Results There were fifty-five patients included and of those, eleven had a documented history of MS. Fluid resuscitation volumes, temperature, heart rate, and mean arterial pressure were similar between groups during the resuscitation period (p > 0.05). LOS was similar between both groups (12, IQR: 2–17 vs. median 16, IQR: 12–21; p = 0.090). However, when normalized to % TBSA burn, patients with MS had a significantly higher median LOS/% TBSA burned (1.2, IQR: 0.7–2.0 vs. 2.1, IQR: 1.1–7.1; p = 0.031). Conclusions Patients with concurrent burn injuries and MS have a significantly longer LOS/% TBSA burn suggesting that more time is required to heal their wounds. Surprisingly, there were no other significant differences in the after the burn acute phase between these two cohorts.

Objective High-frequency, low-amplitude whole-body vibration (WBV) is being used to treat a range of musculoskeletal disorders; however, there is surprisingly limited knowledge regarding its effect(s) on joint tissues. This study was undertaken to examine the effects of repeated exposure to WBV on bone and joint tissues in an in vivo mouse model. Methods Ten-week-old male mice were exposed to vertical sinusoidal vibration under conditions that mimic those used clinically in humans (30 minutes per day, 5 days per week, at 45 Hz with peak acceleration at 0.3g). Following WBV, skeletal tissues were examined by micro–computed tomography, histologic analysis, and immunohistochemistry, and gene expression was quantified using real-time polymerase chain reaction. Results Following 4 weeks of WBV, intervertebral discs showed histologic hallmarks of degeneration in the annulus fibrosus, disruption of collagen organization, and increased cell death. Greater Mmp3 expression in the intervertebral disc, accompanied by enhanced collagen and aggrecan degradation, was found in mice exposed to WBV as compared to controls. Examination of the knee joints after 4 weeks of WBV revealed meniscal tears and focal damage to the articular cartilage, changes resembling osteoarthritis. Moreover, mice exposed to WBV also demonstrated greater Mmp13 gene expression and enhanced matrix metalloproteinase–mediated collagen and aggrecan degradation in articular cartilage as compared to controls. No changes in trabecular bone microarchitecture or density were detected in the proximal tibia. Conclusion Our experiments reveal significant negative effects of WBV on joint tissues in a mouse model. These findings suggest the need for future studies of the effects of WBV on joint health in humans.

A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018.

A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018.

Objective Low-amplitude whole-body vibration has been adopted for the treatment of back pain and spinal disorders. However, there is limited knowledge of the impact of vibration on the intervertebral disc (IVD). This study was undertaken to examine the effects of acute vibration on anabolic and catabolic pathways in the IVD and to characterize the dependence of these changes on time and frequency. Methods Custom-designed platforms were developed to apply acute vibration to ex vivo and in vivo mouse models. Spinal segments (ex vivo) or mice (in vivo) were subjected to vibration (for 30 minutes at 15–90 Hz with peak acceleration at 0.3g), and IVDs were examined at specific time points after vibration. Gene expression was quantified using real-time polymerase chain reaction, and protein levels were examined by quantitative mass spectrometry and immunofluorescence. Results In the ex vivo model, acute vibration at 15 Hz induced expression of anabolic genes (aggrecan, biglycan, decorin, type I collagen, and Sox9) and suppressed expression of Mmp13, with the most pronounced changes detected 6 hours following vibration. These beneficial effects were frequency dependent and were no longer evident between 45 and 90 Hz. In vivo, the effects on anabolic gene expression were even more robust and were accompanied by decreased expression of Adamts4, Adamts5, and Mmp3. Moreover, significant increases in the protein levels of aggrecan, biglycan, decorin, and type I collagen were detected in vivo. Conclusion These findings demonstrate dramatic anabolic effects of acute vibration on IVD tissue, responses that are dependent on frequency. The similarity of the in vivo and ex vivo responses indicates that at least some effects of vibration are tissue autonomous.

© 2016 Osteoarthritis Research Society International Objective Whole-body vibration (WBV) platforms are commercially available devices that are used clinically to treat numerous musculoskeletal conditions based on their reported ability to increase bone mineral density and muscle strength. Despite widespread use, there is an alarming lack of understanding of the direct effects of WBV on joint health. Previous work by our lab demonstrated that repeated exposure to WBV using protocols that model those used clinically, induces intervertebral disc (IVD) degeneration and osteoarthritis-like damage in the knee of skeletally mature, male mice of a single outbred strain (CD-1). The present study examined whether exposure to WBV induces similar deleterious effects in a genetically different strain of mouse (C57BL/6). Design Male 10-week-old C57BL/6 mice were exposed to vertical sinusoidal WBV for 30 min/day, 5 days/week, for 4 or 8 weeks using previously reported protocols (45 Hz, 0.3 g peak acceleration). Following WBV, joint tissues were examined using histological analysis and gene expression was quantified using real-time PCR (qPCR). Results Our analyses show a lack of WBV-induced degeneration in either the knee or IVDs of C57BL/6 mice exposed to WBV for 4 or 8 weeks, in direct contrast to the WBV-induced damage previously reported by our lab in CD-1 mice. Conclusions Together with previous studies from our group, the present study demonstrates that the effects of WBV on joint tissues vary in a strain-specific manner. These findings highlight the need to examine genetic or physiological differences that may underlie susceptibility to the deleterious effects of WBV on joint tissues.

© 2017 Osteoarthritis Research Society International Objective Whole-body vibration (WBV) is a popular fitness trend based on claims of increased muscle mass, weight loss and reduced joint pain. Following its original implementation as a treatment to increase bone mass in patients with osteoporosis, WBV has been incorporated into clinical practice for musculoskeletal disorders, including back pain. However, our recent studies revealed damaging effects of WBV on joint health in a murine model. In this report, we examined potential mechanisms underlying disc degeneration following exposure of mice to WBV. Methods Ten-week-old male mice were exposed to WBV (45 Hz, 0.3 g peak acceleration, 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. Micro-computed tomography (micro-CT), histological, and gene expression analyses were used to assess the effects of WBV on spinal tissues. Results Exposure of mice to 4 or 8 weeks of WBV did not alter total body composition or induce significant changes in vertebral bone density. On the other hand, WBV-induced intervertebral disc (IVD) degeneration, associated with decreased disc height and degenerative changes in the annulus fibrosus (AF) that did not recover within 4 weeks after cessation of WBV. Gene expression analysis showed that WBV for 8 weeks induced expression of Mmp3, Mmp13, and Adamts5 in IVD tissues, changes preceded by increased expression of Il-1β. Conclusions Progressive IVD degeneration induced by WBV was associated with increased expression of Il-1β within the IVD that preceded Mmp and Adamts gene induction. Moreover, WBV-induced IVD degeneration is not reversed following cessation of vibration.

Summary Objective Low-amplitude, high-frequency whole-body vibration (WBV) has been adopted for the treatment of musculoskeletal diseases including osteoarthritis (OA); however, there is limited knowledge of the direct effects of vibration on joint tissues. Our recent studies revealed striking damage to the knee joint following exposure of mice to WBV. The current study examined the effects of WBV on specific compartments of the murine tibiofemoral joint over 8 weeks, including microarchitecture of the tibia, to understand the mechanisms associated with WBV-induced joint damage. Design Ten-week-old male CD-1 mice were exposed to WBV (45 Hz, 0.3 g peak acceleration; 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. The knee joint was evaluated histologically for tissue damage. Architecture of the subchondral bone plate, subchondral trabecular bone, primary and secondary spongiosa of the tibia was assessed using micro-CT. Results Meniscal tears and focal articular cartilage damage were induced by WBV; the extent of damage increased between 4 and 8-week exposures to WBV. WBV did not alter the subchondral bone plate, or trabecular bone of the tibial spongiosa; however, a transient increase was detected in the subchondral trabecular bone volume and density. Conclusions The lack of WBV-induced changes in the underlying subchondral bone suggests that damage to the articular cartilage may be secondary to the meniscal injury we detected. Our findings underscore the need for further studies to assess the safety of WBV in the human population to avoid long-term joint damage.

© 2015 by the authors. All right reserved. The intervertebral disc is a complex structure responsible for flexibility, multi-axial motion, and load transmission throughout the spine. Importantly, degeneration of the intervertebral disc is thought to be an initiating factor for back pain. Due to a lack of understanding of the pathways that govern disc degeneration, there are currently no disease-modifying treatments to delay or prevent degenerative disc disease. This review presents an overview of our current understanding of the developmental processes that regulate intervertebral disc formation, with particular emphasis on the role of the notochord and notochord-derived cells in disc homeostasis and how their loss can result in degeneration. We then describe the role of small animal models in understanding the development of the disc and their use to interrogate disc degeneration and associated pathologies. Finally, we highlight essential development pathways that are associated with disc degeneration and/or implicated in the reparative response of the tissue that might serve as targets for future therapeutic approaches.

SUMMARY Back pain related to intervertebral disc degeneration is the most common musculoskeletal problem, with a lifetime prevalence of 82%. The lack of effective treatment for this widespread problem is directly related to our limited understanding of disc development, maintenance and degeneration. The aim of this study was to determine the developmental origins of nucleus pulposus cells within the intervertebral disc using a novel notochord-specific Cre mouse. To trace the fate of notochordal cells within the intervertebral disc, we derived a notochord-specific Cre mouse line by targeting the homeobox gene Noto. Expression of this gene is restricted to the node and the posterior notochord during gastrulation [embryonic day 7.5 (E7.5)-E12.5]. The Noto-cre mice were crossed with a conditional lacZ reporter for visualization of notochord fate in whole-mount embryos. We performed lineage-tracing experiments to examine the contribution of the notochord to spinal development from E12.5 through to skeletally mature mice (9 months). Fate mapping studies demonstrated that, following elongation and formation of the primitive axial skeleton, the notochord gives rise to the nucleus pulposus in fully formed intervertebral discs. Cellular localization of β-galactosidase (encoded by lacZ) and cytokeratin-8 demonstrated that both notochordal cells and chondrocyte-like nucleus pulposus cells are derived from the embryonic notochord. These studies establish conclusively that notochordal cells act as embryonic precursors to all cells found within the nucleus pulposus of the mature intervertebral disc. This suggests that notochordal cells might serve as tissue-specific progenitor cells within the disc and establishes the Noto-cre mouse as a unique tool to interrogate the contribution of notochordal cells to both intervertebral disc development and disc degeneration.

The nucleus pulposus is an avascular and aneural tissue that has significant influence on the homeostasis and overall function of the intervertebral disc. The nucleus pulposus is comprised of a heterogeneous population of cells including large notochord cells and smaller chondrocyte-like cells. Loss of notochord cells has been correlated with the pathogenesis of disc degeneration and consequently, it has been hypothesized that regeneration of the disc could be mediated by notochord cells. Attempts to grow and expand notochord cells in vitro have thus far been limited by cell availability and ineffective culturing methodologies. As a result, co-culturing techniques have been developed in order to exploit notochord-derived signals for the differentiation of proliferative mesenchymal stem cells. A recent study by Korecki et al. has demonstrated that notochord cell conditioned medium has the ability to differentiate mesenchymal stem cells toward a nucleus pulposus-like fate, producing high levels of glycosaminoglycans and type III collagen. These findings suggest that growth factors and other soluble proteins may be able to stimulate endogenous IVD tissue maintenance in vivo. While this study advances our understanding of intervertebral disc cell-cell interactions, limitations remain in our ability to determine the phenotype of terminally differentiated cells within the nucleus pulposus (ie mature notochord cells) and therefore assess the relevance of differentiated mesenchymal stem cells for disc regeneration. In order for the field to progress, elucidation of the notochord phenotype remains of utmost importance. © 2011 The International CCN Society.

High-frequency, low-amplitude whole-body vibration (WBV) is being used to treat a range of musculoskeletal disorders; however, there is surprisingly limited knowledge regarding its effect(s) on joint tissues. This study was undertaken to examine the effects of repeated exposure to WBV on bone and joint tissues in an in vivo mouse model.Ten-week-old male mice were exposed to vertical sinusoidal vibration under conditions that mimic those used clinically in humans (30 minutes per day, 5 days per week, at 45 Hz with peak acceleration at 0.3g). Following WBV, skeletal tissues were examined by micro-computed tomography, histologic analysis, and immunohistochemistry, and gene expression was quantified using real-time polymerase chain reaction.Following 4 weeks of WBV, intervertebral discs showed histologic hallmarks of degeneration in the annulus fibrosus, disruption of collagen organization, and increased cell death. Greater Mmp3 expression in the intervertebral disc, accompanied by enhanced collagen and aggrecan degradation, was found in mice exposed to WBV as compared to controls. Examination of the knee joints after 4 weeks of WBV revealed meniscal tears and focal damage to the articular cartilage, changes resembling osteoarthritis. Moreover, mice exposed to WBV also demonstrated greater Mmp13 gene expression and enhanced matrix metalloproteinase-mediated collagen and aggrecan degradation in articular cartilage as compared to controls. No changes in trabecular bone microarchitecture or density were detected in the proximal tibia.Our experiments reveal significant negative effects of WBV on joint tissues in a mouse model. These findings suggest the need for future studies of the effects of WBV on joint health in humans.

Objective Currently, our ability to treat intervertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue-specific localization of CCN proteins and to characterize their role in IVD tissues during embryonic development and age-related degeneration by using a mouse model of notochord-specific CCN2 deletion. Methods Expression of CCN proteins was assessed in IVD tissues from wild-type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord-derived tissues, we generated notochord-specific CCN2–null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed. Results Loss of the CCN2 gene in notochord-derived cells disrupted the formation of IVDs in embryonic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly increased levels of type I collagen within the nucleus pulposus. CCN2-knockout mice also had altered expression of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord-specific CCN2 deletion accelerated age-associated degeneration of IVDs. Conclusion Using a notochord-specific gene targeting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age-associated tissue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration.

Currently, our ability to treat intervertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue-specific localization of CCN proteins and to characterize their role in IVD tissues during embryonic development and age-related degeneration by using a mouse model of notochord-specific CCN2 deletion.Expression of CCN proteins was assessed in IVD tissues from wild-type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord-derived tissues, we generated notochord-specific CCN2-null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed.Loss of the CCN2 gene in notochord-derived cells disrupted the formation of IVDs in embryonic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly increased levels of type I collagen within the nucleus pulposus. CCN2-knockout mice also had altered expression of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord-specific CCN2 deletion accelerated age-associated degeneration of IVDs.Using a notochord-specific gene targeting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age-associated tissue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration.

Low-amplitude whole-body vibration has been adopted for the treatment of back pain and spinal disorders. However, there is limited knowledge of the impact of vibration on the intervertebral disc (IVD). This study was undertaken to examine the effects of acute vibration on anabolic and catabolic pathways in the IVD and to characterize the dependence of these changes on time and frequency.Custom-designed platforms were developed to apply acute vibration to ex vivo and in vivo mouse models. Spinal segments (ex vivo) or mice (in vivo) were subjected to vibration (for 30 minutes at 15-90 Hz with peak acceleration at 0.3g), and IVDs were examined at specific time points after vibration. Gene expression was quantified using real-time polymerase chain reaction, and protein levels were examined by quantitative mass spectrometry and immunofluorescence.In the ex vivo model, acute vibration at 15 Hz induced expression of anabolic genes (aggrecan, biglycan, decorin, type I collagen, and Sox9) and suppressed expression of Mmp13, with the most pronounced changes detected 6 hours following vibration. These beneficial effects were frequency dependent and were no longer evident between 45 and 90 Hz. In vivo, the effects on anabolic gene expression were even more robust and were accompanied by decreased expression of Adamts4, Adamts5, and Mmp3. Moreover, significant increases in the protein levels of aggrecan, biglycan, decorin, and type I collagen were detected in vivo.These findings demonstrate dramatic anabolic effects of acute vibration on IVD tissue, responses that are dependent on frequency. The similarity of the in vivo and ex vivo responses indicates that at least some effects of vibration are tissue autonomous.

The purpose of this study was to determine if a power exercise would lead to greater postactivation potentiation (PAP) than a strength exercise, if a 4-or 5-minute rest interval led to greater PAP, the extent to which PAP was an individual phenomenon, and the effect of PAP on the ground reaction force (GRF) during a vertical jump (VJ). Subjects included 16 volleyball athletes (8 men and 8 women) from a Division I university. Participants were instructed to complete a pre-exercise countermovement jump for height. After the VJ, subjects performed 5 repetitions of either the back squat or hang clean (midthigh) with a load equal to their 5 repetition maximum (5RM). After the 5RM resistance exercise, countermovement jumps were completed at 4 or 5 minutes after the back squat or hang clean. Ground reaction force was measured using a force platform embedded in the ground, whereas VJ height was assessed using a Vertec jump apparatus. Data were analyzed using a factorial analysis of variance with repeated measures. Results revealed that there was no consistent rest interval or exercise that produced the largest increase in VJ height for all subjects, and there were no apparent differences because of gender. The condition that produced the largest increase in VJ height for each individual resulted in an average increase of 5.7% (2.72 +/- 1.21 cm; p0.001). There was no significant difference (p0.05) in peak GRF, and no significant correlation (r = -0.110, p = 0.707) between the increase in VJ height and increase in peak GRF. Results suggest that individually determining complex training variables will increase VJ height, thus acutely enhancing athletic performance.

Objective. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in controlling cell differentiation, and that PPAR gamma ligands can modify inflammatory and fibrotic responses. The aim of the present study was to examine the role of PPAR gamma in a mouse model of skin scleroderma, in which mice bearing a fibroblast-specific deletion of PPAR gamma were used.Methods. Cutaneous sclerosis was induced by subcutaneous injection of bleomycin, while untreated control groups were injected with phosphate buffered saline. Mice bearing a fibroblast-specific deletion of PPAR gamma were investigated for changes in dermal thick ness, inflammation, collagen content, and the number of a-smooth muscle actin-positive cells. The quantity of the collagen-specific amino acid hydroxyproline was also measured. In addition, the effect of PPAR gamma deletion on transforming growth factor beta 1 (TGF beta 1) signaling in the fibroblasts was investigated.Results. Bleomycin treatment induced marked cutaneous thickening and fibrosis in all treated mice. Deletion of PPAR gamma resulted in enhanced susceptibility to bleomycin-induced skin fibrosis, as indicated by increases in all measures of skin fibrosis and enhanced sensitivity of fibroblasts to TGF beta 1 in PPAR-deficient mice.Conclusion. These results indicate that PPAR gamma suppresses fibrogenesis. Specific agonists of PPAR gamma may therefore alleviate the extent of the development of cutaneous sclerosis.

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3beta in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic alpha-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3beta pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.

© 2015 McCann et al. Low back pain is the most common musculoskeletal problem and the single most common cause of disability, often attributed to degeneration of the intervertebral disc. Lack of effective treatment is directly related to our limited understanding of the pathways responsible for maintaining disc health. While transcriptional analysis has permitted initial insights into the biology of the intervertebral disc, complete proteomic characterization is required. We therefore employed liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) protein/peptide separation and mass spectrometric analyses to characterize the protein content of intervertebral discs from skeletally mature wild-type mice. A total of 1360 proteins were identified and categorized using PANTHER. Identified proteins were primarily intracellular/plasma membrane (35%), organelle (30%), macromolecular complex (10%), extracellular region (9%). Molecular function categorization resulted in three distinct categories: catalytic activity (33%), binding (molecule interactions) (29%), and structural activity (13%). To validate our list, we confirmed the presence of 14 of 20 previously identified IVD-associated markers, including matrix proteins, transcriptional regulators, and secreted proteins. Immunohistochemical analysis confirmed distinct localization patterns of select protein with the intervertebral disc. Characterization of the protein composition of healthy intervertebral disc tissue is an important first step in identifying cellular processes and pathways disrupted during aging or disease progression.

INTRODUCTION: Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) to specifically catalyze the conversion of prostaglandin (PG) H2 to PGE2. mPGES-1 plays a key role in inflammation, pain and arthritis; however, the role of mPGES-1 in fibrogenesis is largely unknown. Herein, we examine the role of mPGES-1 in a mouse model of skin scleroderma using mice deficient in mPGES-1. METHODS: Wild type (WT) and mPGES-1 null mice were subjected to the bleomycin model of cutaneous skin scleroderma. mPGES-1 expressions in scleroderma fibroblasts and in fibroblasts derived from bleomycin-exposed mice were assessed by Western blot analysis. Degree of fibrosis, dermal thickness, inflammation, collagen content and the number of α-smooth muscle actin (α-SMA)-positive cells were determined by histological analyses. The quantity of the collagen-specific amino acid hydroxyproline was also measured. RESULTS: Compared to normal skin fibroblasts, mPGES-1 protein expression was elevated in systemic sclerosis (SSc) fibroblasts and in bleomycin-exposed mice. Compared to WT mice, mPGES-1-null mice were resistant to bleomycin-induced inflammation, cutaneous thickening, collagen production and myofibroblast formation. CONCLUSIONS: mPGES-1 expression is required for bleomycin-induced skin fibrogenesis. Inhibition of mPGES-1 may be a viable method to alleviate the development of cutaneous sclerosis and is a potential therapeutic target to control the onset of fibrogenesis.

Following publication of our recent article [1], an error in Figure 5d was noticed. In Figure 5d, the β-actin blot corres ponding to α-SMA blot was captured on the chemi luminescence imaging system in an inverted orientation. Since this imager does not capture the protein marker, an error in the orientation of the membrane while capturing the picture of the blot occurred. During preparation of the fi gures for Figure 5d, the α-SMA blot was in right orientation but since orientation of β-actin blot was inverse as it was captured inversely resulted in non-corresponding β-actin blot with respect to α-SMA blot. We have rectifi ed this error now and β-actin blot now corresponds to α-SMA blot. Th e corrected fi gure 5 is given here as Figure 1 and a supplementary fi gure 1 (Additional fi le 1) showing another set of blots representing Figure 5d is also provided.