Bone homeostasis is maintained by osteoclast-mediated bone destruction and osteoblast-mediated bone formation, which are two tightly coupled and controlled processes. Double protection for bones through enhancing osteoblastogenesis but inhibiting osteoclastogenesis becomes a promising strategy for treating osteoporosis. However, there are little small molecular compounds found to regulate bone remodeling balance. We recently examined the effect of wedelolactone, a natural product from Ecliptae herba , on osteoblastogenesis and osteoclastogenesis in vitro and in vivo. Our results revealed that wedelolactone stimulated osteoblast differentiation and bone mineralization in mouse bone marrow mesenchymal stem cells (BMSC). At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. The dual functional role of wedelolactone was mediated through inducing Wnt/GSK-3β/β-catenin pathway in BMSC and inhibiting NF-κB/c-fos/NFATc1 pathway in preosteoclastic RAW264.7 cells. Thus, we found that wedelolacone simultaneously regulated bone resorption and bone formation, and could therefore develop a new class of dual-action therapeutic agents for osteoporosis.
An implant-supported prosthesis can restore masticatory function to patients with missing teeth. A prerequisite for success is to position the implant inserted within sufficient bone to be stably osseointegrated, whilst also allowing the restoration to meet functional and esthetic needs. Unfortunately, prosthesis-driven implant sites are not always characterized by adequate bone dimensions. Furthermore, following tooth extraction, severe bone resorption often occurs. Though an array of surgical techniques are available for bone augmentation, guided bone regeneration (GBR) is one that can produce both functional and esthetic results reproducibly with high success rates, whether performed prior to or simultaneous with implant placement. Given the relevance of barrier membrane material and its individual properties to the success of GBR and, consequently, implant-supported restorations, we compared the clinical performance of a new resorbable non-crosslinked collagen membrane, creos xenoprotect (CXP), with a reference membrane Bio-Gide (BG), for GBR at dehisced implant sites. Results from a prospective, randomized clinical trial (NCT02373787) on 49 patients receiving simultaneous GBR and implant insertion demonstrated that both collagen membranes result in safe bone augmentation of dehiscence defects. Implant survival rate at reentry surgery, 6 months after implant insertion, was 100%. The new CXP membrane was statistically non-inferior to the reference BG membrane with respect to mean difference in bone defect height between implant insertion and reentry surgery ( p <0.001). Moreover, there was no difference in patient pain or quality of life between the two treatment arms. However, there were trends in improved outcomes, namely higher bone gain and lower membrane exposure rates, when CXP was used compared with BG, though not statistically significant. Together, the study confirms that, even using a simultaneous surgical approach, the CXP collagen membrane supports bone regeneration at dehisced implant sites with few complications. This demonstrates that new barrier membrane materials with improved properties, such as CXP, can provide clinical benefits to patients.
Forkhead box subfamily O (FoxO) transcription factors upregulate target genes involved in skeletal muscle metabolism, cellular proliferation, stress resistance, and apoptosis and are regulated by protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation. A recent study demonstrated that the phosphorylation of FoxO3a is directly induced by the overexpression of heat shock protein 72 (Hsp72) in rat soleus muscle; however, whether heat stress treatment induces FoxO3a phosphorylation in rat skeletal muscle remains unclear. Therefore, in this study, we evaluated the effects of heat stress on the regulation of FoxO3a signaling in rat skeletal muscle. Our data revealed that heat stress treatment resulted in a significant increase in FoxO3a phosphorylation (Ser253) in the soleus and plantaris muscles after 24 h. This may be due to upregulation of Hsp72 and activation of the phosphatase and tensin homolog deleted from chromosome 10 (PTEN)/Akt and mitogen-activated protein kinase/ERK kinase (MEK)/ERK pathways. We concluded that heat stress in rat skeletal muscles induces the phosphorylation of FoxO3a and the heat stress-induced FoxO3a phosphorylation may be related to Hsp72 upregulation as well as PTEN/Akt- and MEK/ERK-pathway activation.
Compressive osseointegration fixation using the Compress® is an alternative to traditional intramedullary fixation for endoprosthetic reconstruction. This study aims to evaluate if there is a time delay to achieve stable compressive osseointegration fixation.What is your aim?Current manufacturer recommendations call for 6 weeks of limited weight bearing and limited published research suggests increased early aseptic failure. Between 2006 and 2014, surgeons at one center treated 116 patients with 137 Compress® implants for lower extremity oncologic reconstruction, revision arthroplasty, and fracture nonunion or malunion. Patients were prescribed limited weight bearing for 6 weeks as per manufacturer recommendations and we report on outcome after 116 implants were available for review with a minimum of 2-year follow up (mean 4 years; range 2-9 years). Kaplan-Meier survival plots with 95% Hall-Wellner bands were produced;, survivorship free from overall and aseptic failure at 2 months, 6 months, 1 year and 2 year time points was calculated along with 95% confidence intervals. The relationship with time was further examined via extended Cox pProportion hHazard models. Twenty-seven failures (including 6 aseptic failures) occurred among the 116 implants. Survivorship free from overall failure at 2 months was 92% (95% CI, 84%-100%) for proximal femur reconstructions, 98% (95% CI, 95%-100%) for distal femur reconstructions, and 100% for proximal tibia reconstructions. No aseptic failures were observed prior to 2 months in any group, with the first aseptic failure occurring at 81 days. Extended Cox pProportional hazards modeling demonstrated differences in hazard ratio (HR) by location (p=0.049) with an increased hazard for the proximal tibia group relative to the distal tibia group (HR=4.42, p=0.052) for overall failure but not aseptic mechanical failure. Only the overall failure showed a time dependent interaction (p value=0.008), reflecting that the increased hazard for the proximal tibia group occurred at 4-6 months, with no failures after this point. We were unable to identify a clear temporality for aseptic failure and compressive osseointegration fixation in our patient series and . The 6-week post-operative time point showed no relationship with increased risk of failure. More research is necessary to understand the early biomechanical stability of compressive osseointegration fixation and its ability to withstand physiologic loads, i.e. immediate weight-bearing, prior to biologic osseointegration.
Prolonged skeletal muscle disuse results in muscle atrophy. Currently, no therapeutic treatment is available for the prevention of this problem. Nonetheless, growing evidence suggests that prevention of disuse-induced oxidative stress in inactive muscle fibers can delay inactivity-induced muscle atrophy. We recently tested the hypothesis that dietary supplementation with the antioxidant astaxanthin (AX) might protect against disuse muscle atrophy, in part, by preventing myonuclear apoptosis. Seven-day unloading resulted in reduced soleus muscle weight and myofiber cross-sectional area. However, this decline was suppressed by AX supplementation. Further, AX prevented disuse-induced increase in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei. Our data showed that AX supplementation before and during hindlimb unloading attenuated soleus muscle atrophy, in part, by suppressing myonuclear apoptosis.
Skeletal muscle wasting induced by prolonged periods of muscle disuse due to immobilization, chronic bed rest, physical inactivity, or spaceflight causes dramatic muscle atrophy via multiple signaling pathways. However, the molecular mechanisms of muscle wasting are not completely understood. Histone deacetylase (HDAC) 4 is a central component of muscle transcriptional reprogramming upon denervation. We recently examined the changes in the nuclear expression of HDAC4 and its downstream targets in immobilization-induced rat skeletal muscle atrophy. Nuclear abundance of HDAC4 was found to enhance the transcription of myogenin and MyoD , muscle-specific transcriptional regulators, and induce the expression of atrogin-1, a central component of muscle atrophy. These data demonstrated that the cellular localization of HDAC4 and downstream proteins may play an important role in disuse-induced rat skeletal muscle atrophy.
Equine laminitis is a crippling disease that affects all breeds of horses and is commonly a career-ending and often life-threatening disease. Treatment of laminitis continues to be a controversial topic in equine veterinary medicine because there is a lack of universally efficacious treatment modalities. We recently developed a practical method to efficiently deliver transgene-produced proteins deep within the equine foot. We used recombinant adeno-associated viral vectors (rAAVs) to deliver marker genes through the palmar digital artery. Vector serotypes rAAV2/1, 2/8 and 2/9 all successfully transduced tissues deep within the enclosed confines of the keratinized hoof-wall without disrupting the native architecture of the foot and all displayed similar levels and patterns of transduction. The use of a surfactant-enriched vector diluent increased regional distribution of the vector and improved the transduction in the hoof-wall region. However, all horses that were tested for vector-neutralizing antibodies were positive for serotype-specific neutralizing antibodies to rAAV2/5. This is the first time an rAAV has been successfully used to transduce tissues of the equine distal extremity and provides a positive outlook for the future therapeutic potential of gene therapy in the equine foot.
The objectives of this study were i) to investigate whether a novel biphasic collagen scaffold supports meniscal repair in an ovine meniscal defect model in vivo , ii) to investigate meniscal cell ingrowth and ECM production in an ex-vivo model and iii) to investigate the effect platelet rich plasma (PRP) on the response of meniscal elements to the scaffold. A novel biphasic scaffold (collagen sponge with 300 mm open pores, reinforced with bands of 150 mm internal strengthening fibres) was implanted into a circular defect in the meniscus of adult sheep with and without PRP. Healing in vivo was monitored by longitudinal gait analysis. At 2 and 26 weeks post surgery durometry, histology and immunohistochemistry was performed on recovered menisci. In vitro, ex vivo ovine meniscus/scaffold models were constructed and the effects of PRP on cell migration and extracellular matrix production monitored by cell tracking, protein extraction and Western blotting. In this study we have demonstrated that a novel biphasic collagen scaffold can support meniscal defect repair in an in vivo model and support the ingrowth of meniscal fibrochondrocyte (MFC) in an ex vivo model. In addition we have demonstrated that the addition of PRP significantly enhances MFC migration and ECM production in vitro and promotes rapid defect healing in vivo. This novel biphasic scaffold supports meniscal healing, which is increased in the presence of PRP, likely due to increased MFC migration. Key words : meniscus, scaffold, meniscal fibrochondrocyte, migration, platelet rich plasma
Animal development requires concerted actions of different signaling molecules in order to ensure correctly timed and localized growth and differentiation of tissues. The extracellular matrix often provides guiding cues for signaling proteins such as the glycosaminoglycan heparan sulfate (HS), which is an important regulator of development. HS biosynthesis is a complex series of events, including chain initiation, chain elongation and chain modification. Chain modification comprises N -deacetylation of the N -acetyl-glucosamin (GlcNAc) residues, epimerization of D-glucuronic acid (GlcA) residues to L-iduronic acid (IdoA) and O -sulfation of all sugar units at different positions. None of these reactions is performed to completion along the HS chain, generating cell-type specific patterns of sulfation. It is well-known that loss of HS leads to severe developmental defects and during recent years it has become evident that even alterations in the HS sulfation pattern strongly affect animal development. Interestingly, these patterns do not only depend on the expression of the respective sulfotransferases, but are also strongly affected by N -deacetylation and epimerization of the HS chains. This review focuses on recent work on the HS C5-glucuronyl epimerase (protein GLCE, gene Glce , earlier named Hsepi ) in mouse cartilage development and relates these findings to earlier studies on GLCE function. The sulfation pattern of HS was altered in all Glce deficient tissues, but extent and nature of the changes were different between cell types. In addition, loss of Glce affected multiple signaling pathways depending on the cell type, stressing the importance of HS as a general regulator during animal development. Promoting ligand/receptor interactions as well as shaping morphogen gradients, two important roles of HS, are clearly affected by the loss of Glce in these studies and are further discussed here.
Cell proliferation is usually depressed during hibernation due to its highly energy-consuming nature. However, this process is not depressed all the time, with previous studies finding an increase in cell proliferation in the brain, testis and skeletal muscle tissues of some hibernators during hibernation. In our study, we investigated the relative mRNA expression levels of ZBED1 , an important transcription factor associated with cell proliferation, in five tissues of the greater horseshoe bat across pre-hibernation, deep hibernation and post-hibernation. Increased expression of ZBED1 during deep hibernation was only observed in the brain and skeletal muscle tissues, but not in the other tissues studied, suggesting a tissue-heterogeneity of the cell proliferation. Increased cell proliferation may compensate for tissue damages under stressful conditions during hibernation.
Hypoxia is studied as a common clinical factor and a condition associated with a number of diseases. The responses induced by hypoxia in tissue are hypoxia severity and duration dependent. Compared with other tissues, skeletal muscles are relatively tolerant to hypoxia due to its low oxygen demand and its adaptation to hypoxia during physical exercise. This review focuses on molecular responses of skeletal muscles to hypoxia, with an emphasis on signaling pathway. Based on published work, hypoxia in skeletal muscle induces a number of responses involving energy metabolism, redox metabolism and angiogenesis. Signaling pathways including PI3K/Akt signaling, AMPK/mTOR signaling, HIF-1 signaling as well as Notch signaling are widely involved in these responses. Energy metabolism associated signaling pathways such as PI3K/Akt signaling, AMPK/mTOR signaling are active during hypoxia in skeletal muscles.
Dental implants long term success rely on the establishment of a stable condition. This stability may be negatively influenced by the coexistence of peri-implant pathology, provoking loss of the supporting bone tissue around the implant. A large range in the prevalence of this condition is observed when analyzing different reports in the literature given the different definitions for peri-implant pathology. The background for this investigation was the assumption that peri-implant pathology is a group of multifactorial situations with several potential non-sufficient, non-necessary causes and the absence of risk models to aid the decision process in the maintenance of implant supported restorations. We explored these important aspects and investigated potential risk factors and statistical models for peri-implant pathology based on a model of sufficient and component causes. We found that biological and biomechanical factors can be involved as causal mechanisms of peri-implant pathology. Our study established three different statistical models based on binary conditional regression analysis, with the representative model presenting high sensitivity, specificity and accuracy, providing high positive and negative likelihood ratios. This model will represent a valid tool for the clinician in the maintenance of implant-supported fixed prosthetic rehabilitations.
Bone grafting is often a prerequisite prior to implant placement. Studies evaluating the volume changes of block grafts in the incorporation phase mostly use methodologies that are difficult to apply when assessing large sample sizes. The aim of this study is to validate a new method for volume measurement of block grafts using CT scans for application on future research. Human bone blocks the were fixed with screws on dry skulls simulating a ridge reconstruction. The physical volume the blocks was determined by the water displacement technique and was used as the control group. A method previously described in the literature was tested using the Dicom Works© software. The new method proposed was performed using a tool of the Dental Slice© software. The volume of each block was automatically calculated by the software. The accuracy of each method was assessed using a paired Student’s t-test. There were no statistically significant differences between the methods and the control group. This novel method to three dimensionally measure bone blocks can accurately determine the volume of grafts for maxillary reconstruction. This method can be useful for future studies that aim to evaluate the remodeling of different types of block grafts.
Heat stress has been shown to attenuate reduction in soleus muscle mass and fiber size in various animal models, and it appears likely that heat shock protein 72 (HSP72) plays a key role in heat stress-induced suppression of muscle atrophy. However, there is no evidence that repeated heat stress attenuates the acceleration of apoptotic and proteolytic systems in atrophied rat skeletal muscle. We recently examined the effects of repeated heat stress on muscle atrophy and in terms of apoptosis and proteolysis in unloaded rat skeletal muscle induced by hindlimb unloading. Our results revealed that repeated bouts of heat stress elicited protective effects against disuse atrophy in both soleus and plantaris muscles. Interestingly, this heat stress-induced protection against muscular atrophy may be partially attributed to the suppression of apoptotic activation in slow- and fast-twitch muscles, and decreased ubiquitination in only the soleus muscle. Thus, we have established that repeated heat stress attenuates skeletal muscle atrophy via both upregulation of HSP72 and suppression of apoptotic and proteolytic systems.
Myosin heavy chain isoforms are an important component defining fiber type specific properties in skeletal muscle, such as oxidative versus glycolytic metabolism, rate of contraction, and fatigability. While the molecular mechanisms that underlie specification of the different fiber types are becoming clearer, how this programming becomes disrupted in muscular dystrophy and the functional consequences of fiber type changes in disease are not fully resolved. Fiber type changes in disease, with specific focus on muscular dystrophies caused by defects in the dystrophin glycoprotein complex, are discussed.
Due to limited number of evidence based studies about posterior shoulder dislocations, there is no absolute treatment algotihm. Eventhough variety of classification methods have been proposed, there is lack of a classification method to define treatment. Posterior shoulder dislocations may be seen after specific conditions such as epileptic seizures and electric shock besides high energy traumas. Difficulty in diagnosis complicates the treatment. Treatment approach changes in presence of any fractures. For treatment there are variety of surgical options present such as close reduction, soft tissue based approach and bone based approaches. In this study we are presenting current literature about diagnosis and treatment of posterior shoulder dislocations.
Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the degeneration of motor neurons and subsequent muscular defects. Recent findings have highlighted the contribution of intrinsic skeletal muscle defects to ALS. Research focusing on skeletal muscle disorders might therefore offer alternative routes to the development of new therapeutic options for the treatment of ALS. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein also known as osteoactivin (OA) and dendritic cell-heparin integrin ligand (DC-HIL). GPNMB exerts a protective effect on the central nervous system, and it has been shown to improve memory and to help recovery from reperfusion injury following brain ischemia. In ALS model mice, overexpression of GPNMB prevents motor neuron death and reduces denervation of neuromuscular junctions and atrophy of the skeletal muscles, resulting in a delayed onset of ALS and a longer life span of the animals. When directly injected into skeletal muscle, GPNMB also helps prevent injury of myofibers. These data indicate that GPNMB has a dual site of action against the central nervous system and directly skeletal muscle. Here, we review and highlight recent findings on the effect of GPNMB against ALS, and we discuss remaining challenges of the field and the possible therapeutic applications of GPNMB.
The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway plays critical roles in skeletal development. The impact and underlying mechanisms of its dysregulation in bone homeostasis is poorly defined. The best known and characterized mTOR signaling dysregulation in human disease is called Tuberous Sclerosis Complex (TSC). TSC is an autosomal dominant neurocutaneous syndrome with a high frequency (>66%) of osseous manifestations such as sclerotic lesions in the craniofacial region. TSC is caused by mutations of TSC1 or TSC2, the heterodimer protein inhibitor of mTORC1 signaling. The underlying mechanism of bone lesions in TSC is unclear. We generated a TSC mouse model with TSC1 deletion in neural crest derived (NCD) cells, which recapitulated the sclerotic craniofacial bone lesion in TSC patients. We demonstrated that TSC1 null NCD osteoblasts overpopulated the NCD bones and the resultant increased bone formation is responsible for the sclerotic bone phenotype. Mechanistically, osteoblast number increase is due to the hyperproliferation of osteoprogenitor cells at an early postnatal stage. Noteworthy, administration of rapamycin, an mTORC1 inhibitor at early postnatal stage can completely rescue the excess bone acquisition, but late treatment cannot. Altogether, our data suggested that enhanced mTORC1 signaling in NCD cells can enlarge the osteoprogenitor pool and lead to the excess bone acquisition, which is likely the underlying mechanism of sclerotic bone lesion observed in TSC patients.
Atraumatic shoulder instability (ASI) which is almost always multidirectional, is a condition where the dislocation occurs with minimal or no causative trauma in any direction. It usually occurs due to increased glenohumeral joint volume predominantly as a result of a redundant capsule. Many other factors also do contribute and this has hindered any universally accepted breakthrough in the management plan for such cases. The only consensus has been in the initial treatment which is recommended to be conservative with surgery advised for patients with rehabilitation failure. We review the pathophysiology, clinical assessment, and management strategies of ASI in this article.
Purpose Arthroscopic techniques are becoming the gold standard in the treatment of glenohumeral instability with glenoid bone loss. The purpose of this systematic review is to present the clinical and radiological outcomes following arthroscopic Latarjet procedure. Methods A comprehensive literature systematic review was performed to identify studies reporting clinical and radiographic results of arthroscopic Latarjet procedure. Results Nine articles were selected, which described 512 procedures. Study type, complications, radiographic evaluation, preoperative and postoperative functional scores are identified, analyzed and discussed. Satisfactory results are presented by all authors, and significant postoperative satisfaction with a low rate of dislocation, and accurate graft positioning is reported by all the studies. Conclusion Although high-level evidences are lacking, arthroscopic Latarjet appears to be an effective and safe option to treat glenohumeral instability with bone loss and to provide successful clinical results durable with time. This technique allows accurate graft positioning and satisfactory fusion rate without additional complications compared with open surgery.
