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This study elucidates exposure-response relationships between performance of repetitive tasks, grip strength declines, and fibrogenic-related protein changes in muscles, and their link to inflammation. Specifically, we examined forearm flexor digitorum muscles for changes in connective tissue growth factor (CTGF; a matrix protein associated with fibrosis), collagen type I (Col1; a matrix component), and transforming growth factor beta 1 (TGFB1; an upstream modulator of CTGF and collagen), in rats performing one of two repetitive tasks, with or without anti-inflammatory drugs. To examine the roles of force versus repetition, rats performed either a high repetition negligible force food retrieval task (HRNF), or a high repetition high force handle-pulling task (HRHF), for up to 9 weeks, with results compared to trained only (TR-NF or TR-HF) and normal control rats. Grip strength declined with both tasks, with the greatest declines in 9-week HRHF rats. Quantitative PCR (qPCR) analyses of HRNF muscles showed increased expression of Col1 in weeks 3-9, and CTGF in weeks 6 and 9. Immunohistochemistry confirmed PCR results, and also showed greater increases of CTGF and collagen matrix in 9-week HRHF rats than 9-week HRNF rats. ELISA, and immunohistochemistry revealed greater increases of TGFB1 in TR-HF and 6-week HRHF, compared to 6-week HRNF rats. To examine the role of inflammation, results from 6-week HRHF rats were compared to rats receiving ibuprofen or anti-TNF-α treatment in HRHF weeks 4-6. Both treatments attenuated HRHF-induced increases in CTGF and fibrosis by 6 weeks of task performance. Ibuprofen attenuated TGFB1 increases and grip strength declines, matching our prior results with anti-TNFα. Performance of highly repetitive tasks was associated with force-dependent declines in grip strength and increased fibrogenic-related proteins in flexor digitorum muscles. These changes were attenuated, at least short-term, by anti-inflammatory treatments.

Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteolysis in vivo . Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation. Bone remodeling: Regulation of cells that degrade bone The protein osteoactivin uses an established cell signaling pathway to inhibit the generation of the cells that degrade bone structure. Osteoclast cells break down bone tissue during regular remodeling and repair. Osteoporosis involves an imbalance between this bone degradation and new bone formation. Researchers in the USA led by Fayez Safadi of the Northeast Ohio Medical University studied the effect of osteoactivin on the mouse bone marrow cells that generate osteoclasts. They identified the cell surface protein that osteoactivin binds to when inhibiting osteoclast production. This demonstrates that the inhibitory effect on osteoclast generation is mediated through a well-known intracellular signaling pathway this insight into osteoactivin's regulation of bone remodeling will help researchers to understand and perhaps ultimately control the development of osteoporosis.

A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation. KCI Citation Count: 21

Background Expression of the growth factor osteoactivin (OA) increases during tissue degeneration and regeneration, fracture repair and after denervation-induced disuse atrophy, concomitant with increased matrix metalloproteinases (MMPs). However, OA’s expression with repetitive overuse injuries is unknown. The aim of this study was to evaluate: 1) OA expression in an operant rat model of repetitive overuse; 2) expression of MMPs; 3) inflammatory cytokines indicative of injury or inflammation; and 4) the inducible form of heat shock protein 70 (HSPA1A/HSP72) as the latter is known to increase during metabolic stress and to be involved in cellular repair. Young adult female rats performed a high repetition negligible force (HRNF) food retrieval task for up to 6 weeks and were compared to control rats. Methods Flexor digitorum muscles and tendons were collected from 22 young adult female rats performing a HRNF reaching task for 3 to 6 weeks, and 12 food restricted control (FRC) rats. OA mRNA levels were assessed by quantitative polymerase chain reaction (qPCR). OA, MMP-1, -2, -3, and -13 and HSP72 protein expression was assayed using Western blotting. Immunohistochemistry and image analysis was used to evaluate OA and HSP72 expression. ELISA was performed for HSP72 and inflammatory cytokines. Results Flexor digitorum muscles and tendons from 6-week HRNF rats showed increased OA mRNA and protein expression compared to FRC rats. MMP-1, -2 and -3 progressively increased in muscles whereas MMP-1 and -3 increased in tendons with HRNF task performance. HSP72 increased in 6-week HRNF muscles and tendons, compared to controls, and co-localized with OA in the myofiber sarcolemma. IL-1alpha and beta increased transiently in tendons or muscles in HRNF week 3 before resolving in week 6. Conclusion The simultaneous increases of OA with factors involved in tissue repair (MMPs and HSP72) supports a role of OA in tissue regeneration after repetitive overuse.

ABSTRACT Several reports emphasized the importance of inorganic pyrophosphate (PPi) in hindering osteoblast differentiation and bone matrix mineralization. Its ubiquitous presence is thought to prevent “soft” tissue calcification, whereas its degradation to Pi in bones and teeth by alkaline phosphatase (ALP) may facilitate crystal growth. While the inhibiting role of PPi on osteoblast differentiation and function is largely understood, less is known about its effects on osteoclast determination and activity. In this study, we investigated the role of PPi in bone resorption using calverial organ cultures ex vivo. We present an evidence that PPi stimulated calvarial bone resorption marked by calcium (Ca2+) release in the condition media (CM). We then examined PPi effects on osteoclast differentiation using mouse bone marrow-derived monocytes (BMMs). Our results revealed that PPi enhanced osteoclast differentiation ex vivo, marked by increased number and size of TRAP-stained mature osteoclasts. Moreover, PPi stimulated osteoclastogenesis in BMMs co-cultured with osteoblasts. These data supported the increased osteoclast activity in bone resorption using functional osteo-assays. The finding of PU.1-Egr-1 dependent up-regulation of c-FMS and RANK receptors in BMMs supported the enhanced pre-osteoclast commitment and differentiation. Moreover, osteoclast survival was enhanced by activation of MITF-BCL-2 pathway that was mediated by MAPK-ERK1/2 signaling. Last, our data showed that PPi up-regulated ANK; PPi transporter, during osteoclast differentiation through ERK1/2 phosphorylation whereas mutation of ANK inhibited osteoclastogenesis. Collectively, our data suggest that PPi promotes osteoclast differentiation, survival, and function through PU.1 up-regulation and MITF phosphorylation whereas ANK loss-of-function inhibited osteoclastogenesis. Footnotes * CONFLICT OF INTEREST: The authors have no conflict of interests

Background: Scheduling the arrival of external trucks in container terminals is a critical operational decision that faces both terminal managers and trucking companies. This issue is crucial for both stakeholders since the random arrival of trucks causes congestion in the terminals and extended delays for the trucks. The objective of scheduling external truck appointments is not only to control the workload inside the terminal and the costs resulting from the excessive waiting times of trucks but also, to reduce the truck turnaround time. Methods: A binary programming model was proposed to minimize the waiting time cost, demurrage cost, and container delivery cost. Moreover, a sensitivity analysis was performed to compare various scenarios in terms of cost and to study to what extent the workload level is affected. The mathematical model was solved using Gurobi© 8.1.0 software. Results: 30 instances found in the literature were solved and evaluated in terms of the objective function value (i.e., cost) and truck turnaround time before and after controlling the workload inside the container terminal using the new proposed constraint. Conclusions: The obtained results showed a better distribution of the terminal workload, as well as a lower truck turnaround time that reduces the total cost.

Objective: Systematic reviews are increasingly used as sources of evidence in clinical cardiology guidelines. In the present study, we aimed to assess the quality of published systematic reviews in high impact cardiology journals. Methods: We searched PubMed for systematic reviews published between 2010 and 2019 in five general cardiology journals with the highest impact factor (according to Clarivate Analytics 2019). We extracted data on eligibility criteria, methodological characteristics, bias assessments, and sources of funding. Further, we assessed the quality of retrieved reviews using the AMSTAR tool. Results: A total of 352 systematic reviews were assessed. The AMSTAR quality score was low or critically low in 71% (95% CI: 65.7–75.4) of the assessed reviews. Sixty-four reviews (18.2%, 95% CI: 14.5–22.6) registered/published their protocol. Only 221 reviews (62.8%, 95% CI: 57.6–67.7) reported adherence to the EQUATOR checklists, 208 reviews (58.4%, 95% CI: 53.9–64.1) assessed the risk of bias in the included studies, and 177 reviews (52.3%, 95% CI: 45.1–55.5) assessed the risk of publication bias in their primary outcome analysis. The primary outcome was statistically significant in 274 (79.6%, 95% CI: 75.1–83.6) and had statistical heterogeneity in 167 (48.5%, 95% CI: 43.3–53.8) reviews. The use and sources of external funding was not disclosed in 87 reviews (24.7%, 95% CI: 20.5–29.5). Data analysis showed that the existence of publication bias was significantly associated with statistical heterogeneity of the primary outcome and that complex design, larger sample size, and higher AMSTAR quality score were associated with higher citation metrics. Conclusion: Our analysis uncovered widespread gaps in conducting and reporting systematic reviews in cardiology. These findings highlight the importance of rigorous editorial and peer review policies in systematic review publishing, as well as education of the investigators and clinicians on the synthesis and interpretation of evidence.

This cohort study examines outcomes of patients with brain cancer to provide demographic details on the increase in suicide rate after brain cancer diagnosis.