Publications by authors named "Jessica Cottrell"

29 Publications

  • Page 1 of 1

Local insulin application has a dose-dependent effect on lumbar fusion in a rabbit model.

J Tissue Eng Regen Med 2021 Feb 19. Epub 2021 Feb 19.

Department of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, USA.

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.
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http://dx.doi.org/10.1002/term.3182DOI Listing
February 2021

Zinc chloride affects chondrogenesis via VEGF signaling.

Exp Cell Res 2021 Feb 21;399(2):112436. Epub 2021 Jan 21.

Seton Hall University, South Orange, NJ, 07079, USA. Electronic address:

Insulin mimetics, including zinc containing compounds, have previously been shown to influence chondrogenesis as it relates to healing of fractures in various preclinical models. However, the mechanism by which these compounds drive chondrogenic differentiation is yet undefined. Here, via next-generation sequencing (NGS) and in vitro functional validation, we show that Zinc Chloride (ZnCl) induces expression of both chondrogenic genes (Sox9, Runx1, collagen) as well as genes associated with VEGF-mediated signal transduction, including VEGF receptors 1 and 2 and their ligands; VEGF-A and VEGF-B. Noticeably, although insulin was able to also induce expression of these pro-angiogenic and pro-chondrogenic genes, the impact of insulin on expression of VEGF receptor and ligand genes was marginal when compared to that of ZnCl Furthermore, while the VEGFR antagonist, Axitinib, was able to attenuate the pro-chondrogenic effects of both insulin and ZnCl; a reduction in gene and protein expression was most profoundly observed when the antagonist was applied to cells treated with ZnCl Taken together, these data suggest an important role for the VEGF-mediated signal transduction pathways in the positive effects observed when applying zinc-based compounds as adjuvants for chondrogenesis-mediated fracture healing. In this regard, further mechanistic evaluation of ZnCl and other zinc-containing insulin mimetics may support rational design of therapies targeted for disease indications associated with impaired fracture healing.
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http://dx.doi.org/10.1016/j.yexcr.2020.112436DOI Listing
February 2021

Genetic variants as biomarkers for progression and resistance in multiple myeloma.

Cancer Genet 2021 Apr 6;252-253:1-5. Epub 2020 Dec 6.

Department of Biological Sciences, Seton Hall University, 400 South Orange Ave, South Orange, NJ 07076, USA; Institute for Neuroimmunepharmacology, Seton Hall University, 400 South Orange Ave, South Orange, NJ 07076, USA. Electronic address:

Technical advances in genome sequencing, in particular whole-genome sequencing (WGS), provide adequate tools to understanding cancer at the molecular level while specifically focusing on genetic variants that contribute to the causation and progression of pathogenic cancers. Multiple myeloma (MM), a malignant disease of plasma cells that is marked as rare yet incurable, may be diagnosed by WGS tools, as this cancer is associated with chromosomal translocations and mutations in specific protein-coding genes. Among these protein-coding genes, many are known to be responsible for cell cycle regulation in MM. The initial significant protein-coding mutations were found in NRAS, KRAS and TP53 and later reported in FAM46C, DIS3, CCND1, PNRC1, ALOX12B, HLA-A and MAGED1. Here, we report gene network associations of MM using Qiagen's Ingenuity Pathway Analysis (IPA) software and compared biomarker information reported in IPA for these protein-coding genes (NRAS, TP53 and KRAS). Using Qiagen's Ingenuity Variant Analysis (IVA), we characterized cancer driver variants in MT-ND1 as likely pathogenic or variants of uncertain significance.
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http://dx.doi.org/10.1016/j.cancergen.2020.12.001DOI Listing
April 2021

A meta-analysis of the effect of binge drinking on the oral microbiome and its relation to Alzheimer's disease.

Sci Rep 2020 11 16;10(1):19872. Epub 2020 Nov 16.

Department of Biological Science, Seton Hall University, 400 S Orange Ave, South Orange, NJ, 07079, USA.

The diversity of bacterial species in the oral cavity makes it a key site for research. The close proximity of the oral cavity to the brain and the blood brain barrier enhances the interest to study this site. Changes in the oral microbiome are linked to multiple systemic diseases. Alcohol is shown to cause a shift in the microbiome composition. This change, particularly in the oral cavity, may lead to neurological diseases. Alzheimer's disease (AD) is a common neurodegenerative disorder that may cause irreversible memory loss. This study uses the meta-analysis method to establish the link between binge drinking, the oral microbiome and AD. The QIAGEN Ingenuity Pathway Analysis (IPA) shows that high levels of ethanol in binge drinkers cause a shift in the microbiome that leads to the development of AD through the activation of eIF2, regulation of eIF4 and p70S6K signaling, and mTOR signaling pathways. The pathways associated with both binge drinkers and AD are also analyzed. This study provides a foundation that shows how binge drinking and the oral microbiome dysbiosis lead to permeability changes in the blood brain barrier (BBB), which may eventually result in the pathogenesis of AD.
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http://dx.doi.org/10.1038/s41598-020-76784-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670427PMC
November 2020

CDllb+ targeted depletion of macrophages negatively affects bone fracture healing.

Bone 2020 09 12;138:115479. Epub 2020 Jun 12.

Seton Hall University, South Orange, NJ 07079, United States of America. Electronic address:

Inflammation is an important part of the fracture repair process which requires osteogenic cells to interact with innate immune cells such as macrophages. All murine macrophages express the F4/80 cell surface marker but they may be further subdivided into two main phenotypes: M1 (proinflammatory) or M2 (anti-inflammatory) based on surface marker expression and function. Macrophages polarize between these two main classes in response to inflammation while differentially regulating the healing process. Studies have shown that F4/80+ cell ablation impairs fracture healing, however, the distinct phenotypes that participate in the early healing process is unclear. We hypothesized that the M1 subtype is essential for the early steps of fracture healing and their depletion would impair fracture repair. To test this hypothesis, M1 (F4/80+/MHCII+/CD86+/CDllb+) macrophages were depleted using a saporin conjugated Mac-1 antibody (Mac1SAP) in vitro using primary macrophages and in vivo using a mouse femur fracture model. Primary macrophages isolated from mice femoral bone marrow were either left undifferentiated (+PBS), differentiated into M1 macrophages (+LPS), or differentiated to M2 macrophages (+IL-4), and then treated with either vehicle or 10 pM Mac1SAP. Samples were collected at day 2 and 5 post Mac1SAP treatment. Macrophage subtypes were identified by flow cytometry and cytokine secretion profiles were quantified using xMAP. For the in vivo model, mice were treated with Mac1SAP 24 h prior to fracture. Femur bone marrow samples were collected and analyzed by flow cytometry, xMAP, immunohistochemistry, MicroCT, and histology. The results demonstrated that Mac1SAP significantly depleted M1 macrophages both in vivo and in vitro. Mac1SAP treatment altered expression of 75% of cytokines in vitro and 30% of cytokines in vivo including IL-6, TNF-a, and IP-10. In both the in vitro and in vivo models, the M1 subtype correlated highly with cytokines G-CSF, IL-1α, IL-6, IL-10, LIX, KC, MCP-1, IP-10, MIP1α, MIP1β, RANTES, IL-9, IL-2 and TNFα. M1 depletion was also found to reduced callus properties at day 14 via microCT analysis. Overall, the data suggests that depletion of M1 macrophages by Mac1SAP treatment alters the cytokine expression profiles during early bone repair which ultimately impairs bone healing.
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http://dx.doi.org/10.1016/j.bone.2020.115479DOI Listing
September 2020

Bi-directional Acceleration of Alcohol Use and Opioid Use Disorder.

J Drug Alcohol Res 2019 Oct;2019

Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA.

Alcohol is the most widely used addictive substance. Severe alcohol abuse is diagnosed as "alcohol use disorder" (AUD). A common and harmful drinking pattern is binge drinking that elevates a person's blood alcohol concentration to ≥ 0.08%. Such drinking may be an early indicator of AUD. Opioid misuse and dependence have become worldwide crises. Patterned consumption of various opioids can develop into opioid use disorder (OUD). An intertwined epidemic exists between opioid abuse, alcohol addiction, and binge drinking. Currently, studies on the interaction of AUD and OUD are limited and the underlying mechanisms linking these disorders remains unclear. We reviewed studies on AUD and OUD and utilized Ingenuity Pathway Analysis (IPA) to identify mechanisms of AUD and OUD interaction and potential gene targets for therapeutic agents. According to IPA Canonical Pathways Analysis, Gamma-aminobutyric Acid (GABA) Receptor Signaling, Neuroinflammation Signaling Pathway, Opioid Signaling Pathway and Dopamine-DARPP32 Feedback in cAMP Signaling are potential contributors to the interaction of AUD and OUD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241514PMC
October 2019

Zinc as a Therapeutic Agent in Bone Regeneration.

Materials (Basel) 2020 May 12;13(10). Epub 2020 May 12.

Department of Biological Sciences, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.

Zinc is an essential mineral that is required for normal skeletal growth and bone homeostasis. Furthermore, zinc appears to be able to promote bone regeneration. However, the cellular and molecular pathways through which zinc promotes bone growth, homeostasis, and regeneration are poorly understood. Zinc can positively affect chondrocyte and osteoblast functions, while inhibiting osteoclast activity, consistent with a beneficial role for zinc in bone homeostasis and regeneration. Based on the effects of zinc on skeletal cell populations and the role of zinc in skeletal growth, therapeutic approaches using zinc to improve bone regeneration are being developed. This review focuses on the role of zinc in bone growth, homeostasis, and regeneration while providing an overview of the existing studies that use zinc as a bone regeneration therapeutic.
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http://dx.doi.org/10.3390/ma13102211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287917PMC
May 2020

Kinases: Understanding Their Role in HIV Infection.

World J AIDS 2019 Sep 9;9(3):142-160. Epub 2019 Sep 9.

Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA.

Antiviral drugs currently on the market primarily target proteins encoded by specific viruses. The drawback of these drugs is that they lack antiviral mechanisms that account for resistance or viral mutation. Thus, there is a pressing need for researchers to explore and investigate new therapeutic agents with other antiviral strategies. Viruses such as the human immunodeficiency virus (HIV) alter canonical signaling pathways to create a favorable biochemical environment for infectivity. We used Qiagen Ingenuity Pathway Analysis (IPA) software to review the function of several cellular kinases and the resulting perturbed signaling pathways during HIV infection such as NF-κB signaling. These host cellular kinases such as ADK, PKR, MAP3K11 are involved during HIV infection at various stages of the life cycle. Additionally IPA analysis indicated that these modified host cellular kinases are known to have interactions with each other especially AKT1, a serine/threonine kinase involved in multiple pathways. We present a list of cellular host kinases and other proteins that interact with these kinases. This approach to understanding the relationship between HIV infection and kinase activity may introduce new drug targets to arrest HIV infectivity.
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http://dx.doi.org/10.4236/wja.2019.93011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118713PMC
September 2019

Macrophage subtype and cytokine expression characterization during the acute inflammatory phase of mouse bone fracture repair.

J Orthop Res 2020 08 5;38(8):1693-1702. Epub 2020 Feb 5.

Department of Biological Sciences, Seton Hall University, South Orange, New Jersey.

Fracture repair is a complex process requiring heterotypic interactions between osteogenic cells and immune cells. Recent evidence indicates that macrophages are critically involved in fracture repair. Polarized macrophage populations differentially promote and regulate inflammation in other tissues, but little is known about the various macrophage subtypes and their signaling activities following a bone fracture. The authors hypothesized that classically activated (M1 subtype) and alternatively activated (M2 subtype) macrophages are active during the early repair process to initiate and regulate the inflammatory response. To test our hypothesis, bone marrow was collected from intact femurs (naïve group), contralateral and fractured femurs of mice on days 0, 1, 2, 4, and 7 postfracture. Macrophages were isolated from the bone marrow and macrophage subtypes were identified using flow cytometry with antibodies to F4/80, MHC II, CD86, CD11c, and CD40. Bone marrow cytokine levels were measured using xMAP. Flow cytometry revealed dynamic changes in M1 subtype (F4/80+/MHC II+/CD86+), M2 subtype (F4/80+/MHC II-/CD86-), and dendritic cell (DCs; MHCII+/CD11c+/CD40+) populations following fracture as compared to naïve controls. M1 subtype levels were correlated with IL-1α, IL-1ß, IL-2, IL-17, Eotaxin, and MCP-1, while DCs were correlated with IL-6, G-CSF, LIF, KC, and VEGF-A. The results indicate that M1 and M2 subtypes and DCs are recruited to the fracture site early during the repair process and consequently may work in tandem to regulate the inflammatory response required to recruit osteogenic cells needed for later stages of repair.
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http://dx.doi.org/10.1002/jor.24603DOI Listing
August 2020

Meta-analysis of alcohol induced gut dysbiosis and the resulting behavioral impact.

Behav Brain Res 2019 12 30;376:112196. Epub 2019 Aug 30.

Department of Biological Sciences, Seton Hall University, 400 S Orange Ave, South Orange, NJ, USA; Institute of NeuroImmune Pharmacology (INIP), Seton Hall University, 400 S Orange Ave, South Orange, NJ, USA. Electronic address:

About 99% of the unique genes and almost half of the cells found in the human body come from microbes including bacteria, archaea, fungi, and viruses. Collectively these microorganisms contribute to the microbiome and often reside in the gut. The gut microbiome plays an important role in the body and contributes to digestive health, the immune system, and brain function. The gut microbiome interacts with the central nervous system through the vagal pathways as well as the endocrine or immune pathways. Changes in the proportion or diversity of the microbiota can have an impact on normal physiology and has been implicated in inflammation, depression, obesity, and addiction. Several animal studies suggest the involvement of gut microbiome in the regulation of pain, emotion, and cognition. Alcoholism has been linked with gut microbiome dysbiosis and thus can have deleterious effects on the gut-brain axis balance. Gut microbiome produces important metabolites such as gastrointestinal hormones, short chain fatty acids, precursors to the neuroactive compounds and neurotransmitters that impact the physiology and normal functioning of the body. The microbiome imbalance has been correlated with behavioral changes and alcohol dependence in the host. The objective of this study is to elucidate the link between alcohol induced gut microbiota dysbiosis and any behavioral impact that could incur. A thorough literature search of various databases was conducted to gather data for the alcohol prompted gut microbiome dysbiosis. Ingenuity Pathway Analysis (IPA) software was then utilized to identify links between alcoholism, gut microbiome derived metabolites, and their role in behavior alterations. Overall, this meta-analysis reviews information available on the connection between alcohol induced gut microbiome dysbiosis and the resulting behavioral impact.
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http://dx.doi.org/10.1016/j.bbr.2019.112196DOI Listing
December 2019

A Review of Bioinformatics Tools to Understand Acetaminophen-Alcohol Interaction.

Medicines (Basel) 2019 Jul 25;6(3). Epub 2019 Jul 25.

Department of Biological Science, Seton Hall University, South Orange, NJ 07079, USA.

Drug-ethanol interaction can result in hepatotoxicity. The liver is capable of metabolizing both acetaminophen and ethanol; however, severe acute or moderate chronic simultaneous exposure can cause cell and tissue damage. Therapeutic doses can become harmful if gene activity is altered via competition for metabolic pathways. Simultaneous intake of ethanol and acetaminophen results in overactive CYP2E1 and depletion of glutathione, leaving NAPQI to build up in the liver. NAPQI is a hepatotoxic substance typically neutralized by glutathione. Bioinformatics tools including PharmGKB, Chemical Annotation Retrieval Toolkit, Transcriptome Analysis Console 4.0 (TAC), wikipathways, STRING, and Ingenuity Pathway Analysis (IPA) were used to explore interactive metabolic pathways of ethanol-acetaminophen exposure as a proof of concept for assessing drug-drug or drug-alcohol interactions. As the ethanol-acetaminophen comparison indicates, bioinformatics tools may be used to understand interactive pathways following exposure to ethanol and acetaminophen, with potential extrapolation to other drug-drug/drug-ethanol interactions. Direct interactive effects were not able to be confirmed through this bioinformatics study due to the lack of existing ethanol-acetaminophen simultaneous exposure data. This work suggests that a battery of software applications should be used to assess interactive effects.
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http://dx.doi.org/10.3390/medicines6030079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789846PMC
July 2019

Bone Morphogenetic Proteins (BMPs) and Bone Regeneration.

Methods Mol Biol 2019 ;1891:235-245

Biological Sciences, Seton Hall University, South Orange, NJ, USA.

Many research methods exist to elucidate the role of BMP-2 during bone regeneration. This chapter briefly reviews important animal models used in these studies and provides details on the rat femur defect model. This animal model is frequently utilized to measure the efficacy of osteogenic factors like BMP-2. Detailed information about delivery methods, dose range, and dose duration used in BMP-2-related studies are provided.
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http://dx.doi.org/10.1007/978-1-4939-8904-1_17DOI Listing
June 2019

Common Cell Lines Used to Study Bone Morphogenetic Proteins (BMPs).

Methods Mol Biol 2019 ;1891:1-8

Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA.

Many research methods exist to elucidate the functions of BMPs during osteogenesis. This chapter briefly reviews common immortalized mesenchymal cell types used to measure the efficacy of osteogenic factors like BMP-2. Detailed information regarding media and culture conditions are provided. Parameters relevant to experimental reproducibility and cell line authentication are discussed.
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http://dx.doi.org/10.1007/978-1-4939-8904-1_1DOI Listing
June 2019

Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis.

Viruses 2017 08 8;9(8). Epub 2017 Aug 8.

Department of Biological Sciences, Seton Hall University, South Orange, NJ 07039, USA.

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: , , and . All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence.
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http://dx.doi.org/10.3390/v9080215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580472PMC
August 2017

Effects of local vanadium delivery on diabetic fracture healing.

J Orthop Res 2017 10 8;35(10):2174-2180. Epub 2017 Mar 8.

Department of Orthopaedics, Rutgers New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, New Jersey 07101.

This study evaluated the effect of local vanadyl acetylacetonate (VAC), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, and radiographic scoring were performed, as well as histomorphometry, including percent bone, percent cartilage, and osteoclast numbers. Fractures treated with local 1.5 mg/kg VAC possessed significantly increased mechanical properties compared to controls at 6 weeks post-fracture, including increased torque to failure (15%; p = 0.046), shear modulus (89%; p = 0.043), and shear stress (81%; p = 0.009). The radiographic scoring analysis showed increased cortical bridging at 4 weeks and 6 weeks (119%; p = 0.036 and 209%; p = 0.002) in 1.5 mg/kg VAC treated groups. Histomorphometry of the fracture callus at days 10 and 14 showed increased percent cartilage (121%; p = 0.009 and 45%; p = 0.035) and percent mineralized tissue (66%; p = 0.035 and 58%; p = 0.006) with local VAC treated groups compared to control. Additionally, fewer osteoclasts were observed in the local VAC treated animals as compared to controls at day 14 (0.45% ± 0.29% vs. 0.83% ± 0.36% of callus area; p = 0.032). The results suggest local administration of VAC acts to modulate osteoclast activity and increase percentage of early callus cartilage, ultimately enhancing mechanical properties comparably to non-diabetic animals treated with local VAC. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2174-2180, 2017.
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http://dx.doi.org/10.1002/jor.23521DOI Listing
October 2017

Local Zinc Chloride Release From a Calcium Sulfate Carrier Enhances Fracture Healing.

J Orthop Trauma 2017 Mar;31(3):168-174

*Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, NJ; †Department of Biological Sciences, Seton Hall University, South Orange, NJ; and ‡Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, NJ.

Background: This study examined the efficacy of calcium sulfate (CaSO4) as a carrier for intramedullary delivery of zinc chloride (ZnCl2) to treat fracture healing in a BB Wistar rat model. A non-carrier-mediated injection of 3.0 mg/kg of ZnCl2 has previously been shown to enhance fracture healing.

Methods: A heterogeneous mixture of ZnCl2 and CaSO4 was administered into the intramedullary femoral canal and a mid-diaphyseal femur fracture was created unilaterally. Early and late parameters of fracture healing were assessed using biomechanical testing, radiographic scoring, quantitative histomorphometry (for percentage of new cartilage and bone within the fracture callus), and long-term histologic evaluation.

Results: Fractures treated with 1.0 mg/kg of ZnCl2/CaSO4 demonstrated a significantly higher maximum torque to failure compared with both CaSO4 (P = 0.048) and saline (P = 0.005) controls at 4 weeks postfracture (396.4 versus 251.3 versus 178.7 N mm, respectively). Statistically significant increases in torsional rigidity, effective shear modulus, and effective shear stress were also found, as well as a 3.5 times increase in radiographic score (based on bone union). Histologic examination of the fracture callus indicated enhanced chondrogenesis at day 14 postfracture, with increased percent cartilage for the ZnCl2/CaSO4 group compared with saline (P = 0.0004) and CaSO4 (P = 0.0453) controls. Long-term radiographic and histologic evaluation revealed no abnormal bone formation or infection up to 12 weeks postoperatively.

Conclusions: The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site.
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http://dx.doi.org/10.1097/BOT.0000000000000748DOI Listing
March 2017

The Biology of Bone and Ligament Healing.

Foot Ankle Clin 2016 Dec;21(4):739-761

Department of Orthopaedics, Rutgers-New Jersey Medical School, Medical Sciences Building, Room E-659, 185 South Orange Avenue, Newark, NJ 07103, USA.

This review describes the normal healing process for bone, ligaments, and tendons, including primary and secondary healing as well as bone-to-bone fusion. It depicts the important mediators and cell types involved in the inflammatory, reparative, and remodeling stages of each healing process. It also describes the main challenges for clinicians when trying to repair bone, ligaments, and tendons with a specific emphasis on Charcot neuropathy, fifth metatarsal fractures, arthrodesis, and tendon sheath and adhesions. Current treatment options and research areas are also reviewed.
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http://dx.doi.org/10.1016/j.fcl.2016.07.017DOI Listing
December 2016

Variation in lipid mediator and cytokine levels during mouse femur fracture healing.

J Orthop Res 2016 11 14;34(11):1883-1893. Epub 2016 Mar 14.

Department of Biochemistry and Molecular Biology, Rutgers, the State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103.

Fracture healing is regulated by a variety of inflammatory mediators and growth factors which act over time to regenerate the injured tissue. This study used a mouse femur fracture model to quantify the temporal expression pattern of lipid mediators, cytokines, and related mRNAs during healing. Cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LO) derived lipid mediators, cytokines, and mRNA levels were quantified using mass spectrometry (LC-MS/MS), bead-based multiplex assays (xMAP), and quantitative PCR of cDNA (RTqPCR), respectively. Our analysis found that, the early inflammatory response (between 0 and 4 days after fracture) in the mouse femur fracture model coincided with elevated levels of COX-derived lipid mediators and inflammatory cytokines but with decreased levels of 5-LO-derived lipid mediators. Further, the COX-derived lipid mediators remained elevated for at least 7 days after fracture, suggesting that the COX-derived lipid mediators have additional functions during later phases of the fracture healing response. Differences were also found between mRNA levels and corresponding cytokines and lipid mediator levels, supporting a role for post-transcriptional regulation of gene expression. The temporal changes in fracture callus lipid mediator levels and inflammatory cytokines support a general positive role for inflammatory cytokines and COX-derived lipid mediators on fracture healing and a general negative role for 5-lipoxygenase derived lipid mediators during the initial stages of repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1883-1893, 2016.
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http://dx.doi.org/10.1002/jor.23213DOI Listing
November 2016

Method for measuring lipid mediators, proteins, and messenger RNAs from a single tissue specimen.

Anal Biochem 2015 Jan 20;469:34-42. Epub 2014 Oct 20.

Department of Biochemistry and Molecular Biology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA. Electronic address:

This article describes a new method for extracting RNA, protein, and lipid mediators from a single tissue specimen. Specifically, mouse bone fracture callus specimens were extracted into a single solution that was processed using three different procedures to measure messenger RNA (mRNA) levels by reverse transcription-quantitative polymerase chain reaction (RTqPCR), cytokines and growth factors using an xMAP method, and lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method has several advantages because it decreases the number of animals necessary for experimentation, allows division of the sample from a homogeneous mixture that reduces sample variability, and uses a solution that protects the integrity of the macromolecules during storage.
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http://dx.doi.org/10.1016/j.ab.2014.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257868PMC
January 2015

Local ZnCl2 accelerates fracture healing.

J Orthop Res 2014 Jun 26;32(6):834-41. Epub 2014 Feb 26.

Rutgers New Jersey Medical School, Department of Orthopaedics, 90 Bergen Street, Suite 7300, Newark, New Jersey, 07103.

This study evaluated the effect of local zinc chloride (ZnCl2 ), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, radiographic scoring, histomorphometry, qualitative histological scoring, PCNA immunohistochemistry, and local growth factor analysis were performed. Fractures treated with local ZnCl2 possessed significantly increased mechanical properties compared to controls at 4 weeks post fracture. The radiographic scoring analysis showed increased cortical bridging at 4 weeks in the 1.0 (p=0.0015) and 3.0 (p<0.0001) mg/kg ZnCl2 treated groups. Histomorphometry of the fracture callus at day 7 showed 177% increase (p=0.036) in percent cartilage and 133% increase (p=0.002) in percent mineralized tissue with local ZnCl2 treatment compared to controls. Qualitative histological scoring showed a 2.1× higher value at day 7 in the ZnCl2 treated group compared to control (p = 0.004). Cell proliferation and growth factors, VEGF and IGF-I, within fracture calluses treated with local ZnCl2 were increased at day 7. The results suggest local administration of ZnCl2 increases cell proliferation, causing increased growth factor production which yields improved chondrogenesis and endochondral ossification. Ultimately, these events lead to accelerated fracture healing as early as 4 weeks post fracture.
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http://dx.doi.org/10.1002/jor.22593DOI Listing
June 2014

Development of a guided bone regeneration device using salicylic acid-poly(anhydride-ester) polymers and osteoconductive scaffolds.

J Biomed Mater Res A 2014 Mar 18;102(3):655-64. Epub 2013 May 18.

University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Department of Biochemistry & Molecular Biology, Newark, NJ.

Successful repair of craniofacial and periodontal tissue defects ideally involves a combined therapy that includes inflammation modulation, control of soft tissue infiltration, and bone regeneration. In this study, an anti-inflammatory polymer, salicylic acid-based poly(anhydride-ester) (SAPAE) and a three-dimensional osteoconductive ceramic scaffold were evaluated as a combined guided bone regeneration (GBR) system for concurrent control of inflammation, soft tissue ingrowth, and bone repair in a rabbit cranial defect model. At time periods of 1, 3, and 8 weeks, five groups were compared: (1) scaffolds with a solid ceramic cap (as a GBR structure); (2) scaffolds with no cap; (3) scaffolds with a poly(lactide-glycolide) cap; (4) scaffolds with a slow release SAPAE polymer cap; and (5) scaffolds with a fast release SAPAE polymer cap. Cellular infiltration and bone formation in these scaffolds were evaluated to assess inflammation and bone repair capacity of the test groups. The SAPAE polymers suppressed inflammation and displayed no deleterious effect on bone formation. Additional work is warranted to optimize the anti-inflammatory action of the SAPAE, GBR suppression of soft tissue infiltration, and stimulation of bone formation in the scaffolds and create a composite device for successful repair of craniofacial and periodontal tissue defects.
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http://dx.doi.org/10.1002/jbm.a.34728DOI Listing
March 2014

Effects of local insulin delivery on subperiosteal angiogenesis and mineralized tissue formation during fracture healing.

J Orthop Res 2013 May 13;31(5):783-91. Epub 2012 Dec 13.

Department of Orthopaedics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 90 Bergen Street, Suite 7300, Newark, NJ 07103, USA.

Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1α2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF + cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation.
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http://dx.doi.org/10.1002/jor.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446235PMC
May 2013

The effects of low-intensity pulsed ultrasound upon diabetic fracture healing.

J Orthop Res 2011 Feb 30;29(2):181-8. Epub 2010 Sep 30.

Department of Orthopaedics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA.

In the United States, over 17 million people are diagnosed with type 1 diabetes mellitus (DM) with its inherent morbidity of delayed bone healing and nonunion. Recent studies demonstrate the utility of pulsed low-intensity ultrasound (LIPUS) to facilitate fracture healing. The current study evaluated the effects of daily application of LIPUS on mid-diaphyseal femoral fracture growth factor expression, cartilage formation, and neovascularization in DM and non-DM BB Wistar rats. Polymerase chain reaction (PCR) and ELISA assays were used to measure and quantify growth factor expression. Histomorphometry assessed cartilage formation while immunohistochemical staining for PECAM evaluated neovascularization at the fracture site. In accordance with previous studies, LIPUS was shown to increase growth factor expression and cartilage formation. Our study also demonstrated an increase in fracture callus neovascularization with the addition of LIPUS. The DM group showed impaired growth factor expression, cartilage formation, and neovascularization. However, the addition of LIPUS significantly increased all parameters so that the DM group resembled that of the non-DM group. These findings suggest a potential role of LIPUS as an adjunct for DM fracture treatment.
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http://dx.doi.org/10.1002/jor.21223DOI Listing
February 2011

Osteogenic activity of locally applied small molecule drugs in a rat femur defect model.

J Biomed Biotechnol 2010 16;2010:597641. Epub 2010 Jun 16.

Department of Biochemistry & Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.

The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT) and histomorphometry. In this study, we show that local delivery of alendronate, but not lovastatin or omeprazole, led to significant new bone formation at the defect site. Since alendronate impedes osteoclast-development, it is theorized that alendronate treatment results in a net increase in bone formation by preventing osteoclast mediated remodeling of the newly formed bone and upregulating osteoblasts.
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http://dx.doi.org/10.1155/2010/597641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896701PMC
October 2010

Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion.

J Hand Surg Am 2010 Jun;35(6):941-7

Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, NJ, USA.

Purpose: Besides its anti-inflammatory effects, nonsteroidal anti-inflammatory drug therapy may affect tendon healing and the development of peritendinous adhesions. The purpose of this study was to compare the effect of nonselective (ibuprofen) and COX-2 selective (rofecoxib) nonsteroidal anti-inflammatory drugs on the adhesion formation after tendon repair.

Methods: We assigned 67 rabbits to one of 3 (placebo, ibuprofen, or rofecoxib) groups. The deep flexor tendon was transected, followed by a primary repair. Dosing of the medication began the day after surgery and continued for 27 days. The animals were immobilized in a cast for the first 14 days. Postoperatively, tendon adhesion formation was assessed histologically by calculating the total adhesion in serial axial tendon sections at 3 and 6 weeks and by range of motion measurements at 6 and 12 weeks. We measured range of motion by fixing the metacarpal, applying increasing weight to the free end of the flexor digitorum profundus, and measuring the flexion angle between the metacarpal and the proximal phalanx. Comparison was performed between the treatment groups, as well as to the unoperated forepaws.

Results: Based on histology, we found no difference between the treatment groups when determining the percentage of adhesion between the flexor tendon and its sheath. Control unoperated forepaws had a significantly greater range of metacarpophalangeal joint flexion than the surgically repaired groups. At 12 weeks, range of motion in the ibuprofen group was significantly better than the placebo (p=.009) and rofecoxib (p=.009) groups.

Conclusions: Ibuprofen has a more important effect in limiting adhesion formation compared with rofecoxib after flexor tendon repair. Because ibuprofen inhibits both COX-1 and COX-2, whereas rofecoxib only inhibits COX-2, ibuprofen therapy appears to offer a greater beneficial effect on tendon repair by reducing formation of adhesions.
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http://dx.doi.org/10.1016/j.jhsa.2010.02.033DOI Listing
June 2010

Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Healing.

Pharmaceuticals (Basel) 2010 May 25;3(5):1668-1693. Epub 2010 May 25.

Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07013, USA.

Nonspecific and COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) function by inhibiting the cyclooxygenase isoenzymes and effectively reduce pain and inflammation attributed to acute or chronic musculoskeletal pathologies. However, use of NSAIDs as an analgesic is thought to negatively contribute to bone healing. This review strived to provide a thorough unbiased analysis of the current research conducted on animals and humans regarding NSAIDs and their effect on bone healing. Specifically, this review discusses the role of animal models, dosing regiments, and outcome parameters when examining discrepancies about NSAIDS and their effects on bone regeneration. The role of COX-2 in bone regeneration needs to be better defined in order to further elucidate the impact of NSAIDs on bone healing.
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http://dx.doi.org/10.3390/ph3051668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034003PMC
May 2010

A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing.

Acta Orthop 2009 Oct;80(5):597-605

Department of Biochemistry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.

Background And Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, which is the rate-limiting enzyme in the synthesis of prostaglandins. Previous studies have indicated that NSAID therapy, and in particular NSAIDs that specifically target the inflammatory cyclooxygenase (COX-2), impair bone healing. We compared the effects of ibuprofen and rofecoxib on fibula osteotomy healing in rabbits to determine whether nominal, continuous inhibition of COX-2 with rofecoxib would differentially affect fracture healing more than cyclical inhibition of COX-2 using ibuprofen, which inhibits COX-1 and COX-2 and has a short half-life in vivo.

Methods: Bilateral fibula osteotomies were done in 67 skeletally mature male New Zealand white rabbits. The rabbits were treated with placebo, rofecoxib (12.5 mg once a day), or ibuprofen (50 mg 3 times a day) for 28 days after surgery. Plasma ibuprofen levels were measured by HPLC analysis. Bone healing was assessed by histomorphometry at 3 and 6 weeks after osteotomy, and at 6 and 12 weeks by torsional mechanical testing.

Results: Plasma ibuprofen levels peaked and declined between successive doses. Fracture callus morphology was abnormal in the rofecoxib-treated rabbits and torsional mechanical testing showed that fracture healing was impaired. Ibuprofen treatment caused persistence of cartilage within the fracture callus and reduced peak torque at 6 weeks after osteotomy as compared to the fibulas from the placebo-treated rabbits. In the specimens allowed to progress to possible healing, non-union was seen in 5 of the 26 fibulas from the rofecoxib-treated animals as compared to 1 of 24 in the placebo group and 1 of 30 in the ibuprofen treatment group.

Interpretation: Continuous COX-2 inhibition as modeled by rofecoxib treatment appears to be more deleterious to fracture repair than cyclical cyclooxygenase inhibition as modeled by ibuprofen treatment. Ibuprofen treatment appeared to delay bone healing based upon the persistence of cartilage within the fracture callus and diminished shear modulus. Despite the ibuprofen-induced delay, rofecoxib treatment produced worse fracture (osteotomy) healing than ibuprofen treatment.
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http://dx.doi.org/10.3109/17453670903316769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823333PMC
October 2009

Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing.

J Bone Joint Surg Am 2009 Nov;91(11):2653-65

Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, MSB E-659/Biochem, 185 South Orange Avenue, Newark, NJ 07103, USA.

Background: Loss of cyclooxygenase-2 activity is known to impair fracture-healing in animal models and to inhibit heterotopic ossification in humans. Cyclooxygenase-2 is the rate-limiting enzyme involved in the conversion of arachidonic acid into prostaglandins. Arachidonic acid also is a substrate for 5-lipoxygenase, which catalyzes the initial steps in leukotriene synthesis. In contrast to cyclooxygenase-2, genetic ablation of 5-lipoxygenase accelerates and enhances fracture-healing in mice. The goal of this study was to determine if systemic inhibition of 5-lipoxygenase with an orally delivered drug could accelerate fracture-healing.

Methods: Closed femoral fractures were made in Sprague-Dawley rats. The rats were treated with oral doses of vehicle (ninety-five rats), celecoxib (fifty-nine rats), or AA-861 (a 5-lipoxygenase inhibitor; eighty-nine rats). Fracture-healing was measured with use of radiographs, histomorphometry, and biomechanical testing. Effects of drug treatments on callus cell proliferation and gene expression were determined by incorporation of bromodeoxyuridine and quantitative polymerase chain reactions, respectively.

Results: AA-861 treatment decreased fracture-bridging time, significantly increased early callus cartilage (5.6-fold; p < 0.001) and bone formation (4.2-fold; p = 0.015), and significantly increased callus mechanical properties compared with the vehicle-treated rat fractures. Callus cell proliferation rate was increased by AA-861 treatment, compared with vehicle, at day 2 after fracture (3.68% compared with 2.08%; p < 0.001; 95% confidence interval, -2.81 to -0.039) but was reduced by celecoxib treatment at day 4 after fracture (4.22% compared with 1.84%; p < 0.001; 95% confidence interval, 2.27 to 4.07). At day 10 after fracture, AA-861 and celecoxib treatment increased Type-II collagen mRNA levels (16.0-fold and 6.1-fold, respectively; p < 0.001 for both), but only AA-861 treatment caused an increase in Type-X collagen mRNA (6.3-fold; p < 0.001). AA-861 treatment significantly increased cyclooxygenase-2 (4.0-fold at day 10; p < 0.001) and osteopontin mRNA levels (3.6-fold at day 7; p = 0.024), while decreasing 5-lipoxygenase mRNA levels (5.6-fold at day 4; p < 0.001).

Conclusions: Systemic inhibition of 5-lipoxygenase with an orally delivered drug significantly accelerated and enhanced fracture-healing in this rat model. Gene expression analysis indicates that cyclooxygenase-2 is necessary for callus chondrocytes to progress into hypertrophy so as to complete endochondral ossification. Conversely, inhibition of 5-lipoxygenase alters the inflammatory response, which enhances callus chondrocyte hypertrophy and accelerates endochondral ossification.
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http://dx.doi.org/10.2106/JBJS.H.01844DOI Listing
November 2009

Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing.

Pain 2009 Mar 23;142(1-2):116-26. Epub 2009 Jan 23.

Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School & Graduate School of Biomedical Sciences, MSB E659, 185 S. Orange Avenue, Newark, NJ, USA.

Traditional and COX-2 selective non-steroidal anti-inflammatory drug (NSAID) treatment inhibits fracture healing in animal models. This indicates that either the inflammatory phase following a bone fracture is necessary for efficient or sufficient bone regeneration to heal the fracture or COX-2 may have a specific function during bone regeneration unrelated to inflammation. These observations also indicate that NSAID use during fracture healing may be contra-indicated. Thus, identification of different analgesics for fracture pain or other orthopaedic surgical procedures would be of significant clinical benefit. Inhibitors of p38 kinase also have significant analgesic properties. However, p38 kinase is a critical regulator of inflammation. To assess the potential use of p38 kinase inhibition as a therapeutic strategy to manage fracture pain, the analgesic properties of SCIO-469, a p38alpha kinase inhibitor, were assessed in a rat fracture model and compared to other common analgesics. In addition, the effects of SCIO-469 treatment on ultimate fracture healing outcomes were measured by radiography and torsional mechanical testing. The data indicate that SCIO-469 was an effective analgesic. No adverse events related to fracture healing were observed in rats treated with SCIO-469. Immunohistochemistry showed that p38 kinase is activated primarily in the first days following a fracture. These observations suggest that p38alpha kinase inhibition may be an effective therapeutic strategy to manage orthopaedic-related pain. These observations also indicate that COX-2 has a specific function during bone regeneration other than promoting inflammation.
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http://dx.doi.org/10.1016/j.pain.2008.12.019DOI Listing
March 2009