Musculoskeletal Tissue Research Articles

Adverse event reporting of the IGF-1R monoclonal antibody teprotumumab: a real-world study based on the US food and drug administration adverse event reporting system.

Teprotumumab, an IGF-1R monoclonal antibody, has shown significant efficacy in treating thyroid eye disease (TED). However, since teprotumumab was launched in 2020 and first approved in the United States, there were limited reports of post-marketing adverse events (AEs). In this study, we aimed to mine and analyze the AEs signals with teprotumumab on the basis of the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to provide instructions in clinical practice concerning adverse reactions and assistance in drug development and import/export into other countries. All AE reports were obtained from the FAERS database from the first quarter of 2020 to the fourth quarter of 2023. To comprehensively analyze the AEs, we applied four disproportionality analysis algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms. A total of 687 reports from 200 patients related to administration of teprotumumab were obtained, and 78% of the cases was female. Signal detection of teprotumumab at the system organ class (SOC) level included gastrointestinal disorders, ear and labyrinth disorders, general disorders and administration site conditions, nervous system disorders, and musculoskeletal and connective tissue disorders. AEs that ranked top five at the preferred terms (PTs) level were muscle spasms, fatigue, tinnitus, headache, and deafness. The median time to those AEs onsets was 48days (interquartile range 19.0-92.0days) after administering drugs. Additionally, our results indicated the AEs in reproductive system and breast disorders because the prevalence of TED was more common in women. This study identified many AEs associated with teprotumumab and unveiled potential new AE signals. These results can provide valuable evidence for further clinical application of teprotumumab and are important in enhancing clinical medication safety.

Surgical treatment of the dento-maxillary anomalies in the sagittal plane

Orthognathic surgery involves all surgical interventions to correct musculoskeletal, dental and soft tissue deformities of the jaws, being the treatment method of choice for severe dento–maxillary anomalies, which cannot be rehabilitated by orthodontic treatment alone. The purpose. Evaluation of the particularities of diagnosis and treatment of patients with jaw anomalies in sagittal plane. Material and methods: 22 patients aged between 20 and 46 years, during the period 2016—2021. The surgical stage occurred in stationary conditions, and the clinical and paraclinical evaluation of the patients took place in dental clinic through photostatic examination, study models, radiological examination, intraoral scanning. Results: Predominance of patients with skeletal Class III (77.3%), compared to Class II (22,7%). Osteotomies used: Le Fort 1 for maxilla, osteotomy of the mandibular ramus Obwegeser — Dal Pont for the lower jaw and genioplasty for repositioning the chin. The unavoidable surgical trauma for the correct positioning of the jaws leads to intraoperative hemorrhages, hematomas and postoperative conditions acceptable from the point of view of the endured trauma. Conclusions. The orthodontic–surgical treatment is a safe method of rehabilitating patients with anomalies in sagittal plane, with postsurgical results superior to intraoperative risks and complications.

Real-world non-interventional post-authorization safety study of long-term use of burosumab in children and adolescents with X-linked hypophosphatemia: first interim analysis.

X-linked hypophosphatemia (XLH) is a rare, progressive disorder characterized by excess fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D synthesis. Burosumab is a recombinant human monoclonal antibody that inhibits FGF23, restoring patient serum phosphate levels. Safety data on long-term burosumab treatment are currently limited. This post-authorization safety study (PASS) aims to monitor long-term safety outcomes in children and adolescents (1-17 years) treated with burosumab for XLH. This first interim analysis reports the initial PASS safety outcomes. A 10-year retrospective and prospective cohort study. This PASS utilizes International XLH Registry (NCT03193476) data, which includes standard diagnostic and monitoring practice data at participating European centers. At data cut-off (13 May 2021), 647 participants were included in the International XLH Registry; 367 were receiving burosumab, of which 67 provided consent to be included in the PASS. Mean (SD) follow-up time was 2.2 (1.0) years. Mean (SD) age was 7.3 (4.3) years (range 1.0-17.5 years). Mean duration of burosumab exposure was 29.7 (25.0) months. Overall, 25/67 participants (37.3%) experienced ⩾1 adverse event (AE) during follow-up; 83 AEs were reported. There were no deaths, no AEs leading to treatment withdrawal, nor serious AEs related to treatment. The most frequently reported AEs were classified as 'musculoskeletal and connective tissue disorders', with 'pain in extremity' most frequently reported, followed by 'infections and infestations', with 'tooth abscess' the most frequently reported. In this first interim analysis of the PASS, covering the initial 2 years of data collection, the safety profile of burosumab is consistent with previously reported safety data. The PASS will provide long-term safety data over its 10-year duration for healthcare providers and participants with XLH that contribute to improvements in the knowledge of burosumab safety. European Union electronic Register of Post-Authorisation Studies: EUPAS32190.

Overall prevalence of musculoskeletal and connective tissue diseases in the Volga Federal District during the COVID-19 pandemic

Overall prevalence of musculoskeletal and connective tissue diseases in the Volga Federal District during the COVID-19 pandemic

Vitamin D and childhood disability: diseases of the musculoskeletal system and connective tissue in the Khanty-Mansi Autonomous Okrug - Ugra

Vitamin D deficiency is more prevalent among children with musculoskeletal and connective tissue disorders (MSCTD), which plays a significant role in childhood disability, which ranks sixth in the structure of childhood disability in the Russian Federation. The aim of the research was to study of the relationship between the incidence of childhood disability associated with MSCTD and the state of vitamin D status of the population living in the territory of the Khanty-Mansiysk Autonomous Okrug - Ugra. Material and methods. A correlation analysis was carried out between the level of childhood disability (that arose in connection with MSCTD in children aged 0-17 years in the Khanty-Mansi Autonomous Okrug - Ugra in 2021) and the prevalence of severe vitamin D deficit [serum 25(OH)D <10 ng/ml] among the population (12 city and 5 district municipalities), using the INVITRO-Ural LLC database (31 595 anonymized measurements of vitamin D level in Ugra residents). In addition, a correlation analysis was conducted between the total incidence of certain types of MSCTD in the constituent entities of the Russian Federation and the geographical latitude of the administrative center of the subjects of the Federation. Results. In the Khanty-Mansi Autonomous Okrug - Ugra, the frequency of childhood disability resulting from MSCTD is associated with a statistically stable (p=0.01) directly proportional relationship with the prevalence of severe vitamin D deficit in the residents of the municipality territory. In the Russian Federation, the dependence of the general morbidity of MSCTD in children (arthropathy, juvenile arthritis, and damage to the tendon synovial membranes) is very stable (p<0.0001) directly proportional associated with the geographical latitude of the territory. This indicates the impact of reduced levels of ultraviolet radiation and, accordingly, the average blood level of vitamin D in the population high in latitudes, along with other reasons, on human health. Conclusion. Low levels of vitamin D have a negative impact on the activity of MSCTD in children and the associated disability. To justify the recommended daily dose and duration of vitamin D intake, which in some cases can reduce the activity of MSCTD, it is necessary to measure its initial level in the blood serum of patients at risk.

Surgical treatment of the dento-maxillary anomalies in the sagittal plane

Introduction. Orthognathic surgery involves all surgical interventions to correct musculoskeletal, dental and soft tissue deformities of the jaws, being the treatment method of choice for severe dento–maxillary anomalies, which cannot be rehabilitated by orthodontic treatment alone. The purpose. Evaluation of the particularities of diagnosis and treatment of patients with jaw anomalies in sagittal plane. Material and methods: 22 patients aged between 20 and 46 years, during the period 2016—2021. The surgical stage occurred in stationary conditions, and the clinical and paraclinical evaluation of the patients took place in dental clinic through photostatic examination, study models, radiological examination, intraoral scanning. Results: Predominance of patients with skeletal Class III (77.3%), compared to Class II (22,7%). Osteotomies used: Le Fort 1 for maxilla, osteotomy of the mandibular ramus Obwegeser — Dal Pont for the lower jaw and genioplasty for repositioning the chin. The unavoidable surgical trauma for the correct positioning of the jaws leads to intraoperative hemorrhages, hematomas and postoperative conditions acceptable from the point of view of the endured trauma. Conclusions. The orthodontic–surgical treatment is a safe method of rehabilitating patients with anomalies in sagittal plane, with postsurgical results superior to intraoperative risks and complications.

Comprehensive understanding of the adverse effects associated with temozolomide: a disproportionate analysis based on the FAERS database.

Temozolomide, which is the standard drug for glioma treatment, has several Adverse events (AEs) in the treatment of gliomas and other tumors that are not yet fully understood. This is due to the pharmacological nature of the alkylating agent. A significant proportion of these effects have not been systematically documented or reported. We selected data from the United States FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023. Four algorithms were used for disproportionate analysis, with the objective of assessing the association between temozolomide and related adverse events. In this study, 20,079,906 case reports were collected from the FAERS database, of which 15,152 adverse events related to temozolomide were reported. A total of 352 preferred terms (PTs) and 24 system organ classes (SOCs) that were significantly disproportionally related to the four algorithms were included. The SOCs included blood and lymphatic system disorders (χ2 = 18,220.09, n = 4,325); skin and subcutaneous tissue disorders (χ2 = 408.06, n = 1,347); investigations (χ2 = 639.44, n = 3,925); musculoskeletal and connective tissue disorders (χ2 = 1,317.29, n = 588); and psychiatric disorders (χ2 = 1,098.47, n = 877). PT levels were screened for adverse drug reaction signals consistent with drug inserts, such as anemia, thrombocytopenia, liver function abnormalities, nausea and vomiting, as well as rarely reported adverse drug reactions, such as aplastic anemia, myelodysplastic syndromes, electrolyte disorders, cerebral edema, and high-frequency mutations. The results of our investigation demonstrated both adverse effects that had been reported and a multitude of unreported adverse effects that were serious in nature and lacked a clear cause. These novel findings suggest that more attention should be given to the clinical conditions of patients after treatment to provide a more comprehensive perspective and understanding for further clarifying the safety of temozolomide.

YAP/TAZ as Molecular Targets in Skeletal Muscle Atrophy and Osteoporosis.

Skeletal muscles and bones are closely connected anatomically and functionally. Age-related degeneration in these tissues is associated with physical disability in the elderly and significantly impacts their quality of life. Understanding the mechanisms of age-related musculoskeletal tissue degeneration is crucial for identifying molecular targets for therapeutic interventions for skeletal muscle atrophy and osteoporosis. The Hippo pathway is a recently identified signaling pathway that plays critical roles in development, tissue homeostasis, and regeneration. The Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the mammalian Hippo signaling pathway. This review highlights the fundamental roles of YAP and TAZ in the homeostatic maintenance and regeneration of skeletal muscles and bones. YAP/TAZ play a significant role in stem cell function by relaying various environmental signals to stem cells. Skeletal muscle atrophy and osteoporosis are related to stem cell dysfunction or senescence triggered by YAP/TAZ dysregulation resulting from reduced mechanosensing and mitochondrial function in stem cells. In contrast, the maintenance of YAP/TAZ activation can suppress stem cell senescence and tissue dysfunction and may be used as a basis for the development of potential therapeutic strategies. Thus, targeting YAP/TAZ holds significant therapeutic potential for alleviating age-related muscle and bone dysfunction and improving the quality of life in the elderly.

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for denosumab.

Denosumab is authorized to treat several diseases, including cancer and bone disorders. Nevertheless, its use in clinical practice has been affected by safety concerns. The work retrospectively investigated adverse events (AEs) of denosumab to better understand toxicities. The FAERS data base data from Q1 of 2010 to Q3 of 2023 was chosen. The definition of Medical Dictionary for Regulatory Activities (MedDRA) was dependent on preferred terms (PTs) and system organ class (SOCs). Following the removal of duplicate reports, a disproportionality analysis was conducted to identify safety signals through the calculation of reporting odds ratios (ROR). During the reporting period, 130611 denosumab-related cases were identified; 670pTs with a substantial disproportionality were retained. The connective and musculoskeletal tissue disorders, poisoning, injury, and procedural complications, as well as medical and surgical procedures, were among the important SOCs that satisfied the criteria. Reports at PT levels including off-label use, death, osteonecrosis of the jaw, arthralgia, and pain in extremities were determined. Severe consequences in terms of life-threatening injuries and death accounted for 841 and 19704 cases, respectively of the reported cases. These findings underscore the critical importance of pharmacovigilance and are consistent with established clinical observations. Notably, osteonecrosis of the jaw, arthralgia, pain in extremities, back pain, myalgia, and bone pain were identified as the most prevalent risk signals associated with denosumab.

Therapeutic Potential of Quercetin as an Antioxidant for Bone-Muscle-Tendon Regeneration and Aging.

Quercetin (QC), a naturally occurring bioflavonoid found in various fruits and vegetables, possesses many potential health benefits, primarily attributed to its robust antioxidant properties. The generation of oxidative stress in bone cells is a key modulator of their physiological behavior. Moreover, oxidative stress status influences the pathophysiology of mineralized tissues. Increasing scientific evidence demonstrates that manipulating the redox balance in bone cells might be an effective technique for developing bone disease therapies. The QC antioxidant abilities in skeletal muscle significantly enhance muscle regeneration and reduce muscle atrophy. In addition, QC has been shown to have protective effects against oxidative stress, inflammation, apoptosis, and matrix degradation in tendons, helping to maintain the structural integrity and functionality of tendons. Thus, the antioxidant properties of QC might be crucial for addressing age-related musculoskeletal disorders like osteoporosis, sarcopenia, and tendon-related inflammatory conditions. Understanding how QC influences redox signaling pathways involved in musculoskeletal disorders, including their effect on bone, muscle, and tendon differentiation, might provide insights into the diverse advantages of QC in promoting tissue regeneration and preventing cellular damage. Therefore, this study reviewed the intricate relationship among oxidative stress, inflammation, and tissue repair, affected by the antioxidative abilities of QC, in age-related musculoskeletal tissues to improve the overall health of bones, muscles, and tendons of the skeletal system. Also, reviewing the ongoing clinical trials of QC for musculoskeletal systems is encouraging. Given the positive effect of QC on musculoskeletal health, further scientific investigations and controlled human intervention studies are necessary to explore the therapeutic potential to its optimum strength.

Market Needs and Methodologies Associated with Patient Lipidomic Diagnoses and Analyses.

This chapter conducts an in-depth exploration of the impact of musculoskeletal (MSK) disorders and injuries, with a specific emphasis on their consequences within the older population demographic. It underscores the escalating demand for innovative interventions in MSK tissue engineering. The chapter also highlights the fundamental role played by lipid signaling mediators (LSMs) in tissue regeneration, with relevance to bone and muscle recovery. Remarkably, Prostaglandin E2 (PGE2) emerges as a central orchestrator in these regenerative processes. Furthermore, the chapter investigates the complex interplay between bone and muscle tissues, explaining the important influence exerted by LSMs on their growth and differentiation. The targeted modulation of LSM pathways holds substantial promise as a beneficial way for addressing muscle disorders. In addition to these conceptual understandings, the chapter provides a comprehensive overview of methodologies employed in the identification of LSMs, with a specific focus on the Liquid Chromatography-Mass Spectrometry (LC-MS). Furthermore, it introduces a detailed LC MS/MS-based protocol tailored for the detection of PGE2, serving as an invaluable resource for researchers immersed in this dynamic field of study.

Assessment of Mechanically Induced Changes in Helical Fiber Microstructure Using Diffusion Tensor Imaging.

Noninvasive methods to detect microstructural changes in collagen-based fibrous tissues are necessary to differentiate healthy from damaged tissues in vivo but are sparse. Diffusion Tensor Imaging (DTI) is a noninvasive imaging technique used to quantitatively infer tissue microstructure with previous work primarily focused in neuroimaging applications. Yet, it is still unclear how DTI metrics relate to fiber microstructure and function in musculoskeletal tissues such as ligament and tendon, in part because of the high heterogeneity inherent to such tissues. To address this limitation, we assessed the ability of DTI to detect microstructural changes caused by mechanical loading in tissue-mimicking helical fiber constructs of known structure. Using high-resolution optical and micro-computed tomography imaging, we found that static and fatigue loading resulted in decreased sample diameter and a re-alignment of the macro-scale fiber twist angle similar with the direction of loading. However, DTI and micro-computed tomography measurements suggest microstructural differences in the effect of static versus fatigue loading that were not apparent at the bulk level. Specifically, static load resulted in an increase in diffusion anisotropy and a decrease in radial diffusivity suggesting radially uniform fiber compaction. In contrast, fatigue loads resulted in increased diffusivity in all directions and a change in the alignment of the principal diffusion direction away from the constructs' main axis suggesting fiber compaction and microstructural disruptions in fiber architecture. These results provide quantitative evidence of the ability of DTI to detect mechanically induced changes in tissue microstructure that are not apparent at the bulk level, thus confirming its potential as a noninvasive measure of microstructure in helically architected collagen-based tissues, such as ligaments and tendons.

Micro- and nanostructure specific X-ray tomography reveals less matrix formation and altered collagen organization following reduced loading during Achilles tendon healing

Recovery of the collagen structure following Achilles tendon rupture is poor, resulting in a high risk for re-ruptures. The loading environment during healing affects the mechanical properties of the tendon, but the relation between loading regime and healing outcome remains unclear. This is partially due to our limited understanding regarding the effects of loading on the micro- and nanostructure of the healing tissue. We addressed this through a combination of synchrotron phase-contrast X-ray microtomography and small-angle X-ray scattering tensor tomography (SASTT) to visualize the 3D organization of microscale fibers and nanoscale fibrils, respectively. The effect of in vivo loading on these structures was characterized in early healing of rat Achilles tendons by comparing full activity with immobilization. Unloading resulted in structural changes that can explain the reported impaired mechanical performance. In particular, unloading led to slower tissue regeneration and maturation, with less and more disorganized collagen, as well as an increased presence of adipose tissue. This study provides the first application of SASTT on soft musculoskeletal tissues and clearly demonstrates its potential to investigate a variety of other collagenous tissues. Statement of significanceCurrently our understanding of the mechanobiological effects on the recovery of the structural hierarchical organization of injured Achilles tendons is limited. We provide insight into how loading affects the healing process by using a cutting-edge approach to for the first time characterize the 3D micro- and nanostructure of the regenerating collagen. We uncovered that, during early healing, unloading results in a delayed and more disorganized regeneration of both fibers (microscale) and fibrils (nanoscale), as well as increased presence of adipose tissue. The results set the ground for the development of further specialized protocols for tendon recovery.

Characteristics and Role of Apparent Diffusion Coefficient (ADC) Value in Musculoskeletal Soft Tissue Tumor

Introduction: Musculoskeletal soft tissue tumors (STTs) consist of a group of malignant and benign tumors that present challenges in diagnosis and therapy. Adding diffusion-weighted imaging and apparent diffusion coefficient (DWI/ADC) ​​provides tissue characteristics that are different from those obtained by conventional MR techniques. Quantitative examination of the diffusion of water molecules in tissue is expressed as ADC value, which is expected to be more helpful in differentiating malignant and benign soft tissue masses. This study was carried out to determine the characteristics and role of ADC values ​​in musculoskeletal STTs. Methods: This research was conducted retrospectively. Analysis was performed using MRI results of patients with musculoskeletal STTs who met the inclusion and exclusion criteria. Three regions of interest (ROI) were assessed in the tumor area with the strongest contrast enhancement for DWI mapping, ADC, and ROI ADC value placement. An Independent T-test test was performed to determine the mean difference of ADC in each tumor category. Receiver Operating Characteristics (ROC) were generated to find the optimal cut-off value. Then, a diagnostic test was carried out to determine the sensitivity, specificity, PPV, and NPV of the ADC value. Results: There were 41 research subjects with musculoskeletal STTs with male predominance, in which 75.61% of cases were malignant. DWI/ADC showed that 78.05% of patients with musculoskeletal soft tissue tumors had restricted diffusion areas. In this study, the ADC cutoff value to differentiate benign and malignant musculoskeletal STT is 0,84 x 10-3mm2/s with 77.4% sensitivity and 90% specificity, 96% positive predictive value and 56.3% negative predictive value. Conclusion: In differentiating malignant and benign musculoskeletal STTs, the ADC value provides fair sensitivity, very good specificity, good positive predictive value, and low negative predictive value.

ZnO and Cu/ZnO-modified Magnesium orthopedic implant with improved osteoblast cellular activity: An in-vitro study

Mg-based biomaterials, due to their desirable mechanical integrity, natural bioabsorbability, and osteopromotive characteristics, are promising candidates for both orthopedic applications, such as the surgical fixation of injured musculoskeletal tissues, and cardiovascular applications like coronary artery stents. In the present study, nano- and micro-sized ZnO and Cu/ZnO bioactive particles were used to fabricate Mg-based biocomposites using friction stir processing (FSP). FSP resulted in significant microstructural modification in terms of grain refinement, uniform redistribution of secondary phase particles and homogenous dispersion of bioactive particles. Long-term biodegradation results through H2 evolution method illustrated that biodegradation rate of the bioabsorbable WE43 alloy was significantly reduced by addition of bioactive particles. In addition, fabricated biocomposites with addition of nano-sized particles resulted in lower biodegradation rate in comparison to those with micro-sized particles. Furthermore, uniform dispersion of bioactive particles resulted in superior in-vitro biocompatibility in contact with MC3T3-E1 mouse osteoblast cells. Mg–ZnO–N and Mg–Cu/ZnO–N biocomposites showed improved cell adhesion with elongated and spread morphology of MC3T3-E1 osteoblast cells. Live/dead staining and MTT assay indicated that number of healthy cells and cell viability after 24 h of incubation increased by uniform distribution of bioactive particles. Moreover, fabricated biocomposites with homogenous distribution of Zn2+ and Cu2+ ions showed higher ALP activity. Our findings propose that Mg–ZnO and Mg–Cu/ZnO biocomposites with homogenous dispersion of bioactive particles can be promising candidates for bone tissue regeneration applications.

PH-sensing G protein-coupled orphan receptor GPR68 is expressed in human cartilage and correlates with degradation of extracellular matrix during OA progression

Background Osteoarthritis (OA) is a debilitating joints disease affecting millions of people worldwide. As OA progresses, chondrocytes experience heightened catabolic activity, often accompanied by alterations in the extracellular environment’s osmolarity and acidity. Nevertheless, the precise mechanism by which chondrocytes perceive and respond to acidic stress remains unknown. Recently, there has been growing interest in pH-sensing G protein-coupled receptors (GPCRs), such as GPR68, within musculoskeletal tissues. However, function of GPR68 in cartilage during OA progression remains unknown. This study aims to identify the role of GPR68 in regulation of catabolic gene expression utilizing an in vitro model that simulates catabolic processes in OA. Methods We examined the expression of GPCR by analyzing high throughput RNA-Seq data in human cartilage isolated from healthy donors and OA patients. De-identified and discarded OA cartilage was obtained from joint arthroplasty and chondrocytes were prepared by enzymatic digestion. Chondrocytes were treated with GPR68 agonist, Ogerin and then stimulated IL1β and RNA isolation was performed using Trizol method. Reverse transcription was done using the cDNA synthesis kit and the expression of GPR68 and OA related catabolic genes was quantified using SYBR® green assays. Results The transcriptome analysis revealed that pH sensing GPCR were expressed in human cartilage with a notable increase in the expression of GPR68 in OA cartilage which suggest a potential role for GPR68 in the pathogenesis of OA. Immunohistochemical (IHC) and qPCR analyses in human cartilage representing various stages of OA indicated a progressive increase in GPR68 expression in cartilage associated with higher OA grades, underscoring a correlation between GPR68 expression and the severity of OA. Furthermore, IHC analysis of Gpr68 in murine cartilage subjected to surgically induced OA demonstrated elevated levels of GPR68 in knee cartilage and meniscus. Using IL1β stimulated in vitro model of OA catabolism, our qPCR analysis unveiled a time-dependent increase in GPR68 expression in response to IL1β stimulation, which correlates with the expression of matrix degrading proteases suggesting the role of GPR68 in chondrocytes catabolism and matrix degeneration. Using pharmacological activator of GPR68, our results further showed that GPR68 activation repressed the expression of MMPs in human chondrocytes. Conclusions Our results demonstrated that GPR68 was robustly expressed in human cartilage and mice and its expression correlates with matrix degeneration and severity of OA progression in human and surgical model. GPR68 activation in human chondrocytes further repressed the expression of MMPs under OA pathological condition. These results identify GPR68 as a possible therapeutic target in the regulation of matrix degradation during OA.

Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma.

Heterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation. We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56. In comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group. Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma.

Augmentation of musculoskeletal soft tissue morphology within low back pain patients may suggest the presence of physiological stress shielding: An in vivo study

IntroductionThe pathomechanism of low back pain (LBP) remains unknown. However, changes to mechanical properties of soft tissues affected by LBP may indicate the presence of stress shielding, which may manifest via tissue remodeling. This study investigates the potential for physiological stress shielding within the lumbar spine by examining differences within lumbar soft tissue morphology between control and LBP subjects. MethodsThrough MRI, the total and functional cross-sectional area (tCSA, fCSA) and fatty infiltration (FI) of the lumbar multifidus (MF), erector spinae (ES), quadratus lumborum (QL), psoas major (PM), and thoracolumbar fascia (TLF) were measured from the L1/L2 to L5/S1 intervertebral disc levels of 69 subjects (36 LBP and 33 control subjects). Statistical analysis was conducted using Mann-Whitney U. P < 0.05 denoted significance. ResultsComparison of male LBP patients and male healthy controls yielded an increase in tCSA and fCSA within the L4/L5 PM (p < 0.01), and the L4/L5 ES (p = 0.02) and PM (p < 0.01), respectively, of LBP patients. Female LBP patients’ FI compared to female controls increased within the L1/L2 MF (p = 0.03), L3/L4 MF (p = 0.04) and ES (p = 0.02), and L4/L5 QL (p = 0.01). The L3/L4 TLF also demonstrated an 8% increase in LBP subjects. ConclusionMale patients’ results suggest elevated tissue loading during motion yielding hypertrophy in the L4/L5 ES and PM fCSA, and PM tCSA. Female LBP patients’ MF, ES, and PM at L3/L4 demonstrating elevated FI coupled with TLF tCSA hypertrophy may suggest irregular stress distributions and lay the foundation for stress shielding within musculoskeletal soft tissues.

Trabecular, but not cortical, bone tissue protein synthesis rates are lower in the femoral head when compared to the proximal femur following an intracapsular hip fracture.

All musculoskeletal tissues are in a constant state of turnover, with a dynamic equilibrium between tissue protein synthesis and breakdown rates. The synthesis of protein allows musculoskeletal tissues to heal following injury. Yet, impaired tissue healing is observed following certain injuries, such as geriatric hip fractures. It is assumed that the regenerative properties of femoral head bone tissue are compromised following an intracapsular hip fracture and therefore hip replacement surgery is normally performed. However, the actual impact on in vivo bone protein synthesis rates has never been determined. In the present study, 10 patients (age: 79±10 y, BMI: 24±4kg/m2) with an acute (<24h) intracapsular hip fracture received a primed continuous intravenous infusion of L-[ring-13C6]-phenylalanine before and throughout their hip replacement surgery. Trabecular and cortical bone tissue from both the femoral head and proximal femur were sampled during surgery to assess protein synthesis rates of affected (femoral head) and unaffected (proximal femur) bone tissue, respectively. In addition, tissue samples of gluteus maximus muscle, synovium, ligamentum teres, and femoral head cartilage were collected. Tissue-specific protein synthesis rates were assessed by measuring L-[ring-13C6]-phenylalanine incorporation in tissue protein. Femoral head trabecular bone protein synthesis rates (0.056 [0.024-0.086] %/h) were lower when compared to proximal femur trabecular bone protein synthesis rates (0.081 [0.056-0.118] %/h; P=0.043). Cortical bone protein synthesis rates did not differ between the femoral head and proximal femur (0.041 [0.021-0.078] and 0.045 [0.028-0.073] %/h, respectively; P>0.05). Skeletal muscle, synovium, ligamentum teres, and femoral head cartilage protein synthesis rates averaged 0.080 [0.048-0.089], 0.093 [0.051-0.130], 0.121 [0.110-0.167], and 0.023 [0.015-0.039] %/h, respectively. In contrast to the general assumption that the femoral head is avital after an intracapsular displaced hip fracture in the elderly, our data show that bone protein synthesis is still ongoing in femoral head bone tissue during the early stages following an intracapsular hip fracture in older patients. Nonetheless, trabecular bone protein synthesis rates are lower in the femoral head when compared to the proximal femur in older patients following an acute intracapsular hip fracture. Trial register no: NL9036.

Relationship between klotho and physical function in healthy aging

Epidemiological studies have reported a strong association between circulating Klotho and physical function; however, the cohorts were comprised of older adults with multiple comorbidities. Herein, we examined the relationship between Klotho and physical function in a community-based cohort of healthy adults. In this cross-sectional study, serum Klotho was measured in 80 adults who visited the Musculoskeletal Function, Imaging, and Tissue Resource Core of the Indiana Center for Musculoskeletal Health. Participants (n = 20, 10 [50%] men per group) were chosen into four age groups: 20–34, 35–49, 50–64, and ≥ 65 years, and were further grouped based on performance (low vs. high) on grip strength and chair stand tests. Klotho levels were lower in the ≥ 65 years group (703.0 [189.3] pg/mL; p = 0.022) and the 50–64 years group (722.6 [190.5] pg/mL; p = 0.045) compared to 20–34 years (916.1 [284.8] pg/mL). No differences were observed in Klotho between the low and high performers. The ≥ 65 years group walked a shorter distance during the 6-min walk test (6MWT) compared to 20–34 years (p = 0.005). Klotho was correlated with age (p < 0.001), body fat (p = 0.037), and 6MWT distance (p = 0.022). Klotho levels decline as early as the fifth decade of life, potentially before the onset of age-related impairment in exercise capacity.