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News Article | November 14, 2016
Site: www.sciencedaily.com

Researchers at the University of Rochester Medical Center believe they have identified a new means of enhancing the body's ability to repair its own cells, which they hope will lead to better diagnosis and treatment of traumatic nerve injuries, like those sustained in car accidents, sports injuries, or in combat. In a study published today, the team showed that a drug previously approved for other purposes can 'wake up' damaged peripheral nerves and speed repair and functional recovery after injury. The study appearing in EMBO Molecular Medicine, demonstrates for the first time that 4-aminopyridine (4AP), a drug currently used to treat patients with the chronic nerve disease, multiple sclerosis, has the unexpected property of promoting recovery from acute nerve damage. Although this drug has been studied for over 30 years for its ability to treat chronic diseases, this is the first demonstration of 4AP's benefit in treating acute nerve injury and the first time those benefits were shown to persist after treatment was stopped. Study authors, John Elfar, M.D., associate professor of Orthopaedics, and Mark Noble, Ph.D., Martha M. Freeman, M.D., Professor in Biomedical Genetics, and their laboratory team, found that daily treatment with 4AP promotes repair of myelin, the insulating material that normally surrounds nerve fibers. When this insulation is damaged, as occurs in traumatic peripheral nerve injury, nerve cell function is impaired. These researchers found that 4AP treatment accelerates repair of myelin damage and improvement in nerve function. These findings advance an area of research that has been stagnant for nearly 30 years and may address unmet needs of traumatically injured patients in the future. The current standard of care for traumatic peripheral nerve injury is "watchful waiting" to determine whether a nerve has the ability to spontaneously recover, or if it will require surgery. The problem, says Elfar, a Sports Medicine surgeon specializing in hand, wrist, elbow and shoulder repairs, is that "the patient who may recover is recovering so slowly that nerve-dependent tissues are in jeopardy, and the patient who needs surgery has to wait for weeks for the diagnosis that surgery is appropriate. That delay means that surgery is less effective." Elfar's and Noble's team, which includes Kuang-Ching Tseng, Ph.D., former graduate student in the Center for Musculoskeletal Research at the University of Rochester Medical Center and first author of the study, also found that treating mice with a single dose of 4AP one day after nerve crush injury improved muscle function within an hour. In this model, nerves are damaged, but not completely severed. The team believes this finding may suggest that 4AP could be used immediately after an injury to diagnose whether a nerve is severed, however further studies are required to determine if this will work in humans. If their results can be translated into humans, it could mean earlier and more rapid diagnosis of traumatic peripheral nerve injuries, enabling earlier surgery and better outcomes for patients whose nerves have been completely severed. For patients whose nerves are still connected, 4AP treatment could offer a new means to speed recovery, where none has previously existed. The Department of Defense has recognized the potential impact this could have for soldiers in combat situations and granted $1 million to Elfar and Noble to continue this research over the next three years. "This is an ideal outcome for development of a treatment to promote tissue regeneration," said Noble. "The drug we use to identify injuries that need repair of their insulating myelin is the same drug we use to promote the needed repair. As 4AP has been well-studied in chronic injuries, and is approved for treating multiple sclerosis, the new benefits we discovered can be explored rapidly and much more cheaply than is needed for developing an entirely new drug." Beyond nerve injuries sustained during accidents or in the line of duty, the researchers are also looking into using 4AP to repair nerve conduction after routine surgeries. Removal of the prostate, for example, can cause nerve damage that leaves patients with incontinence and erectile dysfunction, the burden and stigma of which may contribute to prostate cancer patients refusing the surgery. Elfar and Noble hope to begin a clinical trial to test this in the near future. The proposed trial has been approved by the Food and Drug Administration (FDA), and University of Rochester researchers and clinicians are completing the planning stages before recruiting participants.


News Article | November 14, 2016
Site: www.eurekalert.org

Researchers at the University of Rochester Medical Center believe they have identified a new means of enhancing the body's ability to repair its own cells, which they hope will lead to better diagnosis and treatment of traumatic nerve injuries, like those sustained in car accidents, sports injuries, or in combat. In a study published today, the team showed that a drug previously approved for other purposes can 'wake up' damaged peripheral nerves and speed repair and functional recovery after injury. The study appearing in EMBO Molecular Medicine, demonstrates for the first time that 4-aminopyridine (4AP), a drug currently used to treat patients with the chronic nerve disease, multiple sclerosis, has the unexpected property of promoting recovery from acute nerve damage. Although this drug has been studied for over 30 years for its ability to treat chronic diseases, this is the first demonstration of 4AP's benefit in treating acute nerve injury and the first time those benefits were shown to persist after treatment was stopped. Study authors, John Elfar, M.D., associate professor of Orthopaedics, and Mark Noble, Ph.D., Martha M. Freeman, M.D., Professor in Biomedical Genetics, and their laboratory team, found that daily treatment with 4AP promotes repair of myelin, the insulating material that normally surrounds nerve fibers. When this insulation is damaged, as occurs in traumatic peripheral nerve injury, nerve cell function is impaired. These researchers found that 4AP treatment accelerates repair of myelin damage and improvement in nerve function. These findings advance an area of research that has been stagnant for nearly 30 years and may address unmet needs of traumatically injured patients in the future. The current standard of care for traumatic peripheral nerve injury is "watchful waiting" to determine whether a nerve has the ability to spontaneously recover, or if it will require surgery. The problem, says Elfar, a Sports Medicine surgeon specializing in hand, wrist, elbow and shoulder repairs, is that "the patient who may recover is recovering so slowly that nerve-dependent tissues are in jeopardy, and the patient who needs surgery has to wait for weeks for the diagnosis that surgery is appropriate. That delay means that surgery is less effective." Elfar's and Noble's team, which includes Kuang-Ching Tseng, Ph.D., former graduate student in the Center for Musculoskeletal Research at the University of Rochester Medical Center and first author of the study, also found that treating mice with a single dose of 4AP one day after nerve crush injury improved muscle function within an hour. In this model, nerves are damaged, but not completely severed. The team believes this finding may suggest that 4AP could be used immediately after an injury to diagnose whether a nerve is severed, however further studies are required to determine if this will work in humans. If their results can be translated into humans, it could mean earlier and more rapid diagnosis of traumatic peripheral nerve injuries, enabling earlier surgery and better outcomes for patients whose nerves have been completely severed. For patients whose nerves are still connected, 4AP treatment could offer a new means to speed recovery, where none has previously existed. The Department of Defense has recognized the potential impact this could have for soldiers in combat situations and granted $1 million to Elfar and Noble to continue this research over the next three years. "This is an ideal outcome for development of a treatment to promote tissue regeneration," said Noble. "The drug we use to identify injuries that need repair of their insulating myelin is the same drug we use to promote the needed repair. As 4AP has been well-studied in chronic injuries, and is approved for treating multiple sclerosis, the new benefits we discovered can be explored rapidly and much more cheaply than is needed for developing an entirely new drug." Beyond nerve injuries sustained during accidents or in the line of duty, the researchers are also looking into using 4AP to repair nerve conduction after routine surgeries. Removal of the prostate, for example, can cause nerve damage that leaves patients with incontinence and erectile dysfunction, the burden and stigma of which may contribute to prostate cancer patients refusing the surgery. Elfar and Noble hope to begin a clinical trial to test this in the near future. The proposed trial has been approved by the Food and Drug Administration (FDA), and University of Rochester researchers and clinicians are completing the planning stages before recruiting participants. Funding for this study came from the National Institutes of Health, the New York State Spinal Cord Injury Research Program, the American Foundation for Surgery of the Hand, and the Friends of Nancy Lieberman Fund. After the embargo lift, the full study can be accessed at: http://embomolmed.


Shubin A.D.,University of Rochester | Felong T.J.,University of Rochester | Graunke D.,University of Rochester | Ovitt C.E.,University of Rochester | And 2 more authors.
Tissue Engineering - Part A | Year: 2015

More than 40,000 patients are diagnosed with head and neck cancers annually in the United States with the vast majority receiving radiation therapy. Salivary glands are irreparably damaged by radiation therapy resulting in xerostomia, which severely affects patient quality of life. Cell-based therapies have shown some promise in mouse models of radiation-induced xerostomia, but they suffer from insufficient and inconsistent gland regeneration and accompanying secretory function. To aid in the development of regenerative therapies, poly(ethylene glycol) hydrogels were investigated for the encapsulation of primary submandibular gland (SMG) cells for tissue engineering applications. Different methods of hydrogel formation and cell preparation were examined to identify cytocompatible encapsulation conditions for SMG cells. Cell viability was much higher after thiol-ene polymerizations compared with conventional methacrylate polymerizations due to reduced membrane peroxidation and intracellular reactive oxygen species formation. In addition, the formation of multicellular microspheres before encapsulation maximized cell-cell contacts and increased viability of SMG cells over 14-day culture periods. Thiol-ene hydrogel-encapsulated microspheres also promoted SMG proliferation. Lineage tracing was employed to determine the cellular composition of hydrogel-encapsulated microspheres using markers for acinar (Mist1) and duct (Keratin5) cells. Our findings indicate that both acinar and duct cell phenotypes are present throughout the 14 day culture period. However, the acinar:duct cell ratios are reduced over time, likely due to duct cell proliferation. Altogether, permissive encapsulation methods for primary SMG cells have been identified that promote cell viability, proliferation, and maintenance of differentiated salivary gland cell phenotypes, which allows for translation of this approach for salivary gland tissue engineering applications. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Kohn A.,Center for Musculoskeletal Research | Kohn A.,University of Rochester | Dong Y.,Center for Musculoskeletal Research | Mirando A.J.,Center for Musculoskeletal Research | And 5 more authors.
Development | Year: 2012

The Notch signaling pathway has emerged as an important regulator of endochondral bone formation. Although recent studies have examined the role of Notch in mesenchymal and chondro-osteo progenitor cell populations, there has yet to be a true examination of Notch signaling specifically within developing and committed chondrocytes, or a determination of whether cartilage and bone formation are regulated via RBPjκ-dependent or -independent Notch signaling mechanisms. To develop a complete understanding of Notch signaling during cartilage and bone development we generated and compared general Notch gain-of-function (Rosa-NICD f/+), RBPjκ-deficient (Rbpjhf /f), and RBPjκ-deficient Notch gain-of-function (Rosa-NICD f/+;Rbpjhf /f) conditional mutant mice, where activation or deletion of floxed alleles were specifically targeted to mesenchymal progenitors (Prx1Cre) or committed chondrocytes (inducible Col2Cre ERT2). These data demonstrate, for the first time, that Notch regulation of chondrocyte maturation is solely mediated via the RBPjκ-dependent pathway, and that the perichodrium or osteogenic lineage probably influences chondrocyte terminal maturation and turnover of the cartilage matrix. Our study further identifies the cartilage-specific RBPjκ-independent pathway as crucial for the proper regulation of chondrocyte proliferation, survival and columnar chondrocyte organization. Unexpectedly, the RBPjκ-independent Notch pathway was also identified as an important long-range cell non-autonomous regulator of perichondral bone formation and an important cartilage-derived signal required for coordinating chondrocyte and osteoblast differentiation during endochondral bone development. Finally, cartilage-specific RBPjκ-independent Notch signaling likely regulates Ihh responsiveness during cartilage and bone development. © 2012. Published by The Company of Biologists Ltd.


Park D.,Massachusetts General Hospital | Park D.,Harvard Stem Cell Institute | Park D.,Harvard University | Spencer J.A.,Massachusetts General Hospital | And 13 more authors.
Cell Stem Cell | Year: 2012

Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered clinical application despite little definition of their function in residence. Here, we report genetic pulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiring replenishment from bone-marrow-derived, Mx1 + stromal cells with "MSC" features. These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Single cell transplantation yielded progeny that both preserve progenitor function and differentiate into osteoblasts, producing new bone. They are capable of local and systemic translocation and serial transplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineage restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be a heterogeneous population with the Mx1 + population, representing a highly dynamic and stress responsive stem/progenitor cell population of fate-restricted potential that feeds the high cell replacement demands of the adult skeleton. © 2012 Elsevier Inc.


Beier E.E.,University of Rochester | Sheu T.-J.,University of Rochester | Dang D.,University of Rochester | Holz J.D.,University of Rochester | And 4 more authors.
Journal of Biological Chemistry | Year: 2015

Exposure to lead (Pb) from environmental sources remains an overlooked and serious public health risk. Starting in childhood, Pb in the skeleton can disrupt epiphyseal plate function, constrain the growth of long bones, and prevent attainment of a high peak bone mass, all of which will increase susceptibility to osteoporosis later in life. We hypothesize that the effects of Pb on bone mass, in part, come from depression of Wnt/β-catenin signaling, a critical anabolic pathway for osteoblastic bone formation. In this study, we show that depression of Wnt signaling by Pb is due to increased sclerostin levels in vitro and in vivo. Downstream activation of the β-catenin pathway using a pharmacological inhibitor of GSK-3β ameliorates the Pb inhibition of Wnt signaling activity in the TOPGAL reporter mouse. The effect of Pb was determined to be dependent on sclerostin expression through use of the SOST gene knock-out mice, which are resistant to Pb-induced trabecular bone loss and maintain their mechanical bone strength. Moreover, isolated bone marrow cells from the sclerostin null mice show improved bone formation potential even after exposure to Pb. Also, our data suggest that the TGFβ canonical signaling pathway is the mechanism by which Pb controls sclerostin production. Taken together these results support our hypothesis that the osteoporotic-like phenotype observed after Pb exposure is, in part, regulated through modulation of the Wnt/β-catenin pathway. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Xie R.,Center for Musculoskeletal Research | Jiang R.,University of Rochester | Chen D.,Center for Musculoskeletal Research
Genesis | Year: 2011

Axin1 is a critical negative regulator of the canonical Wnt-signaling pathway. It is a concentration-limiting factor in the β-catenin degradation complex. Axin1 null mutant mouse embryos died at embryonic day 9.5, precluding direct genetic analysis of the roles of Axin1 in many developmental and physiological processes using these mutant mice. In this study, we have generated mice carrying two directly repeated loxP sites flanking the exon 2 region of the Axin1 gene. We show that floxed-allele-carrying mice (Axin1 fx/fx) mice appear normal and fertile. Upon crossing the Axin1 fx/fx mice to the CMV-Cre transgenic mice, the loxP-flanked exon 2 region that encodes the N-terminus and the conserved regulation of G-protein signaling domain was efficiently deleted by Cre-mediated excision in vivo. Moreover, we show that mouse embryos homozygous for the Cre/loxP-mediated deletion of exon 2 of the Axin1 gene display embryonic lethality and developmental defects similar to those reported for Axin1 -/- mice. Thus, this Axin1 fx/fx mouse model will be valuable for systematic tissue-specific dissection of the roles of Axin1 in embryonic and postnatal development and diseases. © 2010 Wiley-Liss, Inc.


PubMed | University of Rochester, Center for Musculoskeletal Research and D'Youville College
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2016

The heavy metal lead (Pb) has a deleterious effect on skeletal health. Because bone mass is maintained through a balance of bone formation and resorption, it is important to understand the effect of Pb levels on osteoblastic and osteoclastic activity. Pb exposure is associated with low bone mass in animal models and human populations; however, the correlation between Pb dosing and corresponding bone mass has been poorly explored. Thus, mice were exposed to increasing Pb and at higher levels (500ppm), there was unexpectedly an increase in femur-tibial bone mass by 3 months of age. This is contrary to several studies alluded to earlier. Increased bone volume (BV) was accompanied by a significant increase in cortical thickness of the femur and trabecular bone that extended beyond the epiphyseal area into the marrow cavity. Subsequent evaluations revealed an increase in osteoclast numbers with high Pb exposure, but a deficiency in osteoclastic activity. These findings were substantiated by observed increases in levels of the resorption-altering hormones calcitonin and estrogen. In addition we found that pro-osteoclastic nuclear factor-kappa beta (NF-B) pathway activity was dose dependently elevated with Pb, both invivo and invitro. However, the ability of osteoclasts to resorb bone was depressed in the presence of Pb in media and within test bone wafers. These findings indicate that exposure to high Pb levels disrupts early life bone accrual that may involve a disruption of osteoclast activity. This study accentuates the dose dependent variation in Pb exposure and consequent effects on skeletal health.


News Article | September 27, 2016
Site: www.biosciencetechnology.com

Researchers at Washington University in St. Louis have made headway on a potential treatment for osteoarthritis, which affects up to 27 million people in the United States, using nanoparticles to quash inflammation and protect cartilage. This type of arthritis occurs when the protective tissue at the ends of bones, known as cartilage, gradually erodes, and pain associated with the condition worsens over time. While anti-inflammatory drugs, or steroid injections can alleviate some pain, there is no cure for the cartilage being worn down and effects of medications are not experienced long-term. Scientists in the recent study injected mice locally into the joint, within 24 hours after an injury, with nanoparticles carrying a modified peptide that is able to bind to a molecule called small interfering RNA (siRNA) and block inflammation, decreasing the damage of cartilage. Patients with osteoarthritis usually experienced some earlier type of injury which often results in strong inflammation around the joints.  The nanoparticles were able to lessen inflammation in the injured joints of mice, and unlike other treatments that are short-lived, the nanoparticles penetrate deep into tissues and stayed in the cartilage cells in joints for weeks, the team reported. “I see a lot of patients with osteoarthritis, and there’s really no treatment,” senior author Christine Pham, M.D., associate professor of medicine said in a university release. “We try to treat their symptoms, but even when we inject steroids into an arthritic joint, the drug only remains for up to a few hours, and then it’s cleared. These nanoparticles remain in the joint longer and help prevent cartilage degeneration.” The findings, published Sept. 26 in the Proceedings of the National Academy of Sciences, suggest that if nanoparticle injections are given quickly following a joint injury, it could potentially prevent the development of osteoarthritis. Further studies need to be done to see if this method could help people who already have osteoarthritis and have lost a lot of cartilage. “The inflammatory molecule that we’re targeting not only causes problems after an injury, but it’s also responsible for a great deal of inflammation in advanced cases of osteoarthritis,” Linda Sandell, Ph.D., director of Washington University’s Center for Musculoskeletal Research, said in a statement. “So we think these nanoparticles may be helpful in patients who already have arthritis, and we’re working to develop experiments to test that idea.”


News Article | October 3, 2016
Site: www.chromatographytechniques.com

Osteoarthritis is a debilitating condition that affects at least 27 million people in the United States, and at least 12 percent of osteoarthritis cases stem from earlier injuries. Over-the-counter painkillers, such as anti-inflammatory drugs, help reduce pain but do not stop unrelenting cartilage destruction. Consequently, pain related to the condition only gets worse. Now, researchers at Washington University School of Medicine in St. Louis have shown in mice that they can inject nanoparticles into an injured joint and suppress inflammation immediately following an injury, reducing the destruction of cartilage. The findings are reported online Sept. 26 in the early edition of the Proceedings of the National Academy of Sciences. “I see a lot of patients with osteoarthritis, and there’s really no treatment,” said senior author Christine Pham, MD, an associate professor of medicine. “We try to treat their symptoms, but even when we inject steroids into an arthritic joint, the drug only remains for up to a few hours, and then it’s cleared. These nanoparticles remain in the joint longer and help prevent cartilage degeneration.” Frequently, an osteoarthritis patient has suffered an earlier injury — a torn meniscus or ACL injury in the knee, a fall, car accident or other trauma. The body naturally responds to such injuries in the joints with robust inflammation. Patients typically take drugs such as acetaminophen and ibuprofen, and as pain gets worse, injections of steroids also can provide pain relief, but their effects are short-lived. In this study, the nanoparticles were injected shortly after an injury, and within 24 hours, the nanoparticles were at work taming inflammation in the joint. But unlike steroid injections that are quickly cleared, the particles remained in cartilage cells in the joints for weeks. The nanoparticles used in the study are more than 10 times smaller than a red blood cell, which helps them penetrate deeply into tissues. The particles carry a peptide derived from a natural protein called melittin that has been modified to enable it to bind to a molecule called small interfering RNA (siRNA). The melittin delivers siRNA to the damaged joint, interfering with inflammation in cells. The peptide-based nanoparticle was designed by study co-investigators Hua Pan, PhD, an assistant professor of medicine, and Samuel Wickline, MD, the James R. Hornsby Family Professor of Biomedical Sciences. “The nanoparticles are injected directly into the joint, and due to their size, they easily penetrate into the cartilage to enter the injured cells,” Wickline said. “Previously, we’ve delivered nanoparticles through the bloodstream and shown that they inhibit inflammation in a model of rheumatoid arthritis. In this study, they were injected locally into the joint and given a chance to penetrate into the injured cartilage.” The nanoparticles were injected shortly after injury to prevent the cartilage breakdown that eventually leads to osteoarthritis. Whether such a strategy will work years after an injury, when osteoarthritis is established and there is severe cartilage loss, still needs to be studied.  But the findings suggest that the nanoparticles, if given soon after joint injuries occur, could help maintain cartilage viability and prevent the progression to osteoarthritis. “The inflammatory molecule that we’re targeting not only causes problems after an injury, but it’s also responsible for a great deal of inflammation in advanced cases of osteoarthritis,” said Linda J. Sandell, the Mildred B. Simon Research Professor of Orthopaedic Surgery and director of Washington University’s Center for Musculoskeletal Research. “So we think these nanoparticles may be helpful in patients who already have arthritis, and we’re working to develop experiments to test that idea.”

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