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Albagli A, Rath E, Druckmann I, Efrima B, Kazum E, Parnes N, Sandler AB, Tyler J, Amar E. Pre-injection local anesthesia does not affect experienced pain in intra-articular hip injections. World J Orthop 2025; 16:101197. [PMID: 40027959 PMCID: PMC11866109 DOI: 10.5312/wjo.v16.i2.101197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/02/2025] [Accepted: 01/17/2025] [Indexed: 02/12/2025] Open
Abstract
BACKGROUND Intra-articular hip injections (IAHIs) are commonly used for diagnostic and therapeutic purposes but are often associated with patient anxiety and fear. The disparity between anticipated and experienced pain during IAHIs and the role of pre-injection local anesthesia in pain modulation remains unclear. AIM To investigate the difference between anticipated and experienced pain during IAHIs and the impact of pre-injection local anesthesia. METHODS This prospective study enrolled 60 patients undergoing IAHI, 30 receiving pre-injection superficial local anesthesia and 30 serving as a control group without pre-injection local anesthesia. Pain levels were assessed using numeric rating scales. RESULTS Patients significantly overestimated anticipated pain compared to experienced pain (6.43 ± 2.48 vs 3.68 ± 2.37, P < 0.001). Pre-injection local anesthesia did not significantly reduce experienced pain (3.19 ± 2.38 vs 4.20 ± 2.29, P = 0.130). CONCLUSION Patients overestimate anticipated pain during IAHIs. Pre-injection local anesthesia does not reduce experienced pain.
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Affiliation(s)
- Assaf Albagli
- Department of Orthopedic, Tel Aviv Medical Center, Tel Aviv-Yafo 6801298, Tel Aviv, Israel
| | - Ehud Rath
- Department of Orthopedic, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
| | - Ido Druckmann
- Department of Radiology, Tel Aviv Medical Center, Tel Aviv-Yafo 6801298, Tel Aviv, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo 6801298, Tel Aviv, Israel
| | - Ben Efrima
- Department of Orthopedic, Tel Aviv Medical Center, Tel Aviv-Yafo 6801298, Tel Aviv, Israel
| | - Efi Kazum
- Department of Orthopedic, Tel Aviv Medical Center, Tel Aviv-Yafo 6801298, Tel Aviv, Israel
| | - Nata Parnes
- Department of Orthopedic Surgery, Carthage Area Hospital, Carthage, NY 13619, United States
| | - Alexis B Sandler
- Department of Orthopedic Surgery, Texas Tech University Health Sciences-El Paso, El Paso, TX 79905, United States
| | - John Tyler
- Department of Orthopedic Surgery, Carthage Area Hospital, Carthage, NY 13619, United States
- Department of Orthopedic Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States
| | - Eyal Amar
- Department of Orthopedic, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
- Department of Orthopedic, Tel Aviv University, Tel Aviv 62308, Israel
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Wei X, Li M, You J, Luo J, Zhai J, Zhang J, Feng J, Wang H, Zhou Y. A Procedural Overview of the Involvement of Small Molecules in the Nervous System in the Regulation of Bone Healing. Int J Nanomedicine 2025; 20:1263-1284. [PMID: 39906525 PMCID: PMC11792627 DOI: 10.2147/ijn.s505677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
Clinically, a multitude of factors can contribute to the development of bone defects. In the process of bone healing, the nervous system plays a vital role in bone regeneration. Small molecules from the nervous system, such as neurotrophic factors and neuropeptides, have been found to stimulate osteoblast proliferation and differentiation by activating signaling pathways associated with bone calcification and angiogenesis. These small molecules play a crucial regulatory role at various stages of bone healing. The systematic release mechanism of small molecules within the nervous system through diverse bone tissue engineering materials holds significant clinical implications for the controlled regulation of the bone healing process. This review provides an overview of the involvement of various nervous system small molecules at different stages of bone healing and discusses their regulatory mechanisms, aiming to establish a theoretical foundation for programmed regulation in bone regeneration and design of replacement materials in bone tissue engineering.
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Affiliation(s)
- Xuyan Wei
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Mucong Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaqian You
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaxin Luo
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jingjie Zhai
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiameng Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jian Feng
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Hanchi Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
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Mathew S, Ashraf S, Shorter S, Tozzi G, Koutsikou S, Ovsepian SV. Neurobiological Correlates of Rheumatoid Arthritis and Osteoarthritis: Remodelling and Plasticity of Nociceptive and Autonomic Innervations in Synovial Joints. Neuroscientist 2024:10738584241293049. [PMID: 39668598 DOI: 10.1177/10738584241293049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
Swelling, stiffness, and pain in synovial joints are primary hallmarks of osteoarthritis and rheumatoid arthritis. Hyperactivity of nociceptors and excessive release of inflammatory factors and pain mediators play a crucial role, with emerging data suggesting extensive remodelling and plasticity of joint innervations. Herein, we review structural, functional, and molecular alterations in sensory and autonomic axons wiring arthritic joints and revisit mechanisms implicated in the sensitization of nociceptors, leading to chronic pain. Sprouting and reorganization of sensory and autonomic fibers with the invasion of ectopic branches into surrounding inflamed tissues are associated with the upregulation of pain markers. These changes are frequently complemented by a phenotypic switch of sensory and autonomic profiles and activation of silent axons, inferring homeostatic adjustments and reprogramming of innervations. Identifying critical molecular players and neurobiological mechanisms underpinning the rewiring and sensitization of joints is likely to elucidate causatives of neuroinflammation and chronic pain, assisting in finding new therapeutic targets and opportunities for interventions.
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Affiliation(s)
- Sharon Mathew
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
| | - Sadaf Ashraf
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
- Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, Kent, UK
| | - Susan Shorter
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
| | - Gianluca Tozzi
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
| | - Stella Koutsikou
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
- Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, Kent, UK
| | - Saak V Ovsepian
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime, Kent, UK
- Faculty of Medicine, Tbilisi State University, Tbilisi, Republic of Georgia
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Mobasheri A, Rannou F, Ivanavicius S, Conaghan PG. Targeting the TRPV1 pain pathway in osteoarthritis of the knee. Expert Opin Ther Targets 2024; 28:843-856. [PMID: 39450875 DOI: 10.1080/14728222.2024.2416961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 10/11/2024] [Indexed: 10/26/2024]
Abstract
INTRODUCTION The growing prevalence and lack of effective pain therapies for knee osteoarthritis (KOA) results in a substantial unmet need for novel analgesic therapies. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed in subsets of nociceptive sensory neurons and has major roles in pain transmission and regulation. In the structures of the knee joint, nociceptors are present in abundance. AREAS COVERED TRPV1-expressing nociceptors in the knee represent a rational target to modulate activity at the origin of the pain pathway in KOA and may avoid systemic side effects seen with currently available analgesics. TRPV1 antagonists can induce analgesia, but hyperthermia and thermal hypesthesia side effects have limited their utility. Clinical development of TRPV1 agonists for pain management has progressed further than that of TRPV1 antagonists. Capsaicin and resiniferatoxin have provided proof-of-concept for the modulation of TRPV1 activity in KOA. EXPERT OPINION Intra-articular administration of TRPV1 agonists enables direct delivery to target nerve terminals in the knee, offering a potentially transformative approach for the management of pain associated with KOA. Here, we explore the advances in understanding innervation of the knee joint in KOA, the role of TRPV1-expressing neurons and progress in developing TRPV1 modulators for KOA.
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Affiliation(s)
- Ali Mobasheri
- Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
- Department of Joint Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Université de Liège, Liège, Belgium
| | - François Rannou
- UFR de Médecine, Faculté de Santé, Université Paris Cité, Paris, France
- Service de Rééducation et de Réadaptation de l'Appareil Locomoteur et des Pathologies du Rachis, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France
- INSERM UMR-S 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs (T3S), Campus Saint-Germain-des-Prés, Paris, France
| | | | - Philip G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
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Vincent TL, Miller RE. Molecular pathogenesis of OA pain: Past, present, and future. Osteoarthritis Cartilage 2024; 32:398-405. [PMID: 38244717 PMCID: PMC10984780 DOI: 10.1016/j.joca.2024.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/05/2024] [Accepted: 01/16/2024] [Indexed: 01/22/2024]
Abstract
OBJECTIVE To provide a historical perspective and narrative review on research into the molecular pathogenesis of osteoarthritis pain. DESIGN PubMed databases were searched for combinations of "osteoarthritis", "pain" and "animal models" for papers that represented key phases in the history of osteoarthritis pain discovery research including epidemiology, pathology, imaging, preclinical modeling and clinical trials. RESULTS The possible anatomical sources of osteoarthritis pain were identified over 50 years ago, but relatively slow progress has been made in understanding the apparent disconnect between structural changes captured by radiography and symptom severity. Translationally relevant animal models of osteoarthritis have aided in our understanding of the structural and molecular drivers of osteoarthritis pain, including molecules such as nerve growth factor and C-C motif chemokine ligand 2. Events leading to persistent osteoarthritis pain appear to involve a two-step process involving changes in joint innervation, including neo-innervation of the articular cartilage, as well as sensitization at the level of the joint, dorsal root ganglion and central nervous system. CONCLUSIONS There remains a great need for the development of treatments to reduce osteoarthritis pain in patients. Harnessing all that we have learned over the past several decades is helping us to appreciate the important interaction between structural disease and pain, and this is likely to facilitate development of new disease modifying therapies in the future.
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Affiliation(s)
- Tonia L Vincent
- Centre for OA Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, OX3 7FY Oxford, UK.
| | - Rachel E Miller
- Division of Rheumatology and Chicago Center on Musculoskeletal Pain, Rush University Medical Center, Chicago, IL, USA.
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Liebmann K, Castillo MA, Jergova S, Best TM, Sagen J, Kouroupis D. Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal. Cells 2024; 13:484. [PMID: 38534328 PMCID: PMC10969778 DOI: 10.3390/cells13060484] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.
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Affiliation(s)
- Kevin Liebmann
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Mario A. Castillo
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Stanislava Jergova
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
| | - Jacqueline Sagen
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Morris AJ, Parker RS, Nazzal MK, Natoli RM, Fehrenbacher JC, Kacena MA, White FA. Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair. Curr Osteoporos Rep 2024; 22:193-204. [PMID: 38236511 PMCID: PMC10912155 DOI: 10.1007/s11914-023-00846-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2023] [Indexed: 01/19/2024]
Abstract
PURPOSE OF REVIEW The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system's critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. RECENT FINDINGS Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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Affiliation(s)
- Ashlyn J Morris
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Reginald S Parker
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Murad K Nazzal
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Roman M Natoli
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jill C Fehrenbacher
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
- Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
| | - Fletcher A White
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
- Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA.
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Tokumoto M, Nakasa T, Nekomoto A, Ishikawa M, Ikuta Y, Miyaki S, Adachi N. Expression of calcitonin gene-related peptide induces ligament degeneration through endochondral ossification in osteoarthritis. Int J Rheum Dis 2023; 26:1932-1941. [PMID: 37452551 DOI: 10.1111/1756-185x.14840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 12/11/2022] [Accepted: 07/04/2023] [Indexed: 07/18/2023]
Abstract
AIM Osteoarthritis (OA) is a disease in which degeneration occurs in various tissues such as cartilage and subchondral bone. Degeneration of ligaments also plays an important role in OA progression, resulting in an increase in chondrocytes and ossification, but the factor that causes this is still unclear. It is reported that the expression of calcitonin gene-related peptide (CGRP) increases OA progression, and CGRP might play a role in ligament degeneration because CGRP has a function in endochondral ossification. The purpose of this study is to analyze the mechanism of ligament degeneration and the function of CGRP. METHODS To examine the relationship between ligament degeneration and CGRP expression, human posterior cruciate ligaments (PCL) from OA patients, and senescence-accelerated mouse prone 8 (SAMP8) mice were histologically analyzed. The effect of CGRP on human ligament cells on chondrogenesis, osteogenesis, and adipogenesis was also examined. RESULTS In human PCL and SAMP8 mice, CGRP expression increased as degeneration progressed, and decreased in severe degeneration. CGRP was expressed in the chondrocyte-like cells with SOX9. CGRP-positive cells expressing type II collagen increased with OA progression. CGRP upregulated the gene expression of VEGF, SOX9, RUNX2, COL10a1, and MMP13 in the human ligament cells. CGRP also promoted chondrogenesis and osteogenesis from the human ligament cells. CONCLUSION During OA progression, CGRP plays a role in the transdifferentiation from ligament cells to chondrocytes and promotes endochondral ossification in the ligament. CGRP would be the therapeutic target to prevent ligament degeneration.
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Affiliation(s)
- Maya Tokumoto
- Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Nakasa
- Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
- Medical Center for Translation and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Akinori Nekomoto
- Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Masakazu Ishikawa
- Department of Artificial Joints and Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasunari Ikuta
- Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Shigeru Miyaki
- Medical Center for Translation and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Nobuo Adachi
- Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Nekomoto A, Nakasa T, Ikuta Y, Ding C, Miyaki S, Adachi N. Feasibility of administration of calcitonin gene-related peptide receptor antagonist on attenuation of pain and progression in osteoarthritis. Sci Rep 2023; 13:15354. [PMID: 37717108 PMCID: PMC10505157 DOI: 10.1038/s41598-023-42673-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023] Open
Abstract
Suppressing inflammation and abnormal subchondral bone turnover is essential for reducing osteoarthritis (OA) progression and pain relief. This study focused on calcitonin gene-related peptide (CGRP), which is involved in inflammation and bone metabolism, and investigated whether a CGRP receptor antagonist (rimegepant) could suppress OA progression and relieve pain in two OA models. C57BL/6 mice (10-week-old) underwent surgical destabilization of the medial meniscus, and Rimegepant (1.0 mg/kg/100 μL) or phosphate-buffered saline (100 μL) was administered weekly intraperitoneally after OA surgery and evaluated at 4, 8, and 12 weeks. In the senescence-accelerated mice (SAM)-prone 8 (SAMP8), rimegepant was administered weekly before and after subchondral bone sclerosis and sacrificed at 9 and 23 weeks, respectively. Behavioral assessment and immunohistochemical staining (CGRP) of the dorsal root ganglion (DRG) were conducted to assess pain. In DMM mice, synovitis, cartilage degeneration, and osteosclerosis were significantly suppressed in the rimegepant group. In SAMP8, synovitis, cartilage degeneration, and osteosclerosis were significantly suppressed by rimegepant at 9 weeks; however, not at 23 weeks. Behavioral assessment shows the traveled distance and the number of standings in the rimegepant group were significantly longer and higher. In addition, CGRP expression of the DRG was significantly lower in the rimegepant group at 8 and 12 weeks of DMM and 9 weeks of SAMP8 treatment. No adverse effects were observed in either of the mouse models. Inhibition of CGRP signaling has the potential to be a therapeutic target to prevent OA progression and suppress pain through the attenuation of subchondral bone sclerosis and synovitis.
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Affiliation(s)
- Akinori Nekomoto
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Tomoyuki Nakasa
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan.
| | - Yasunari Ikuta
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Chenyang Ding
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Shigeru Miyaki
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Nobuo Adachi
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
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Ita ME, Singh S, Troche HR, Welch RL, Winkelstein BA. Intra-articular MMP-1 in the spinal facet joint induces sustained pain and neuronal dysregulation in the DRG and spinal cord, and alters ligament kinematics under tensile loading. Front Bioeng Biotechnol 2022; 10:926675. [PMID: 35992346 PMCID: PMC9382200 DOI: 10.3389/fbioe.2022.926675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/27/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic joint pain is a major healthcare challenge with a staggering socioeconomic burden. Pain from synovial joints is mediated by the innervated collagenous capsular ligament that surrounds the joint and encodes nociceptive signals. The interstitial collagenase MMP-1 is elevated in painful joint pathologies and has many roles in collagen regulation and signal transduction. Yet, the role of MMP-1 in mediating nociception in painful joints remains poorly understood. The goal of this study was to determine whether exogenous intra-articular MMP-1 induces pain in the spinal facet joint and to investigate effects of MMP-1 on mediating the capsular ligament’s collagen network, biomechanical response, and neuronal regulation. Intra-articular MMP-1 was administered into the cervical C6/C7 facet joints of rats. Mechanical hyperalgesia quantified behavioral sensitivity before, and for 28 days after, injection. On day 28, joint tissue structure was assessed using histology. Multiscale ligament kinematics were defined under tensile loading along with microstructural changes in the collagen network. The amount of degraded collagen in ligaments was quantified and substance P expression assayed in neural tissue since it is a regulatory of nociceptive signaling. Intra-articular MMP-1 induces behavioral sensitivity that is sustained for 28 days (p < 0.01), absent any significant effects on the structure of joint tissues. Yet, there are changes in the ligament’s biomechanical and microstructural behavior under load. Ligaments from joints injected with MMP-1 exhibit greater displacement at yield (p = 0.04) and a step-like increase in the number of anomalous reorganization events of the collagen fibers during loading (p ≤ 0.02). Collagen hybridizing peptide, a metric of damaged collagen, is positively correlated with the spread of collagen fibers in the unloaded state after MMP-1 (p = 0.01) and that correlation is maintained throughout the sub-failure regime (p ≤ 0.03). MMP-1 injection increases substance P expression in dorsal root ganglia (p < 0.01) and spinal cord (p < 0.01) neurons. These findings suggest that MMP-1 is a likely mediator of neuronal signaling in joint pain and that MMP-1 presence in the joint space may predispose the capsular ligament to altered responses to loading. MMP-1-mediated pathways may be relevant targets for treating degenerative joint pain in cases with subtle or no evidence of structural degeneration.
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Affiliation(s)
- Meagan E. Ita
- Spine Pain Research Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Sagar Singh
- Spine Pain Research Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Harrison R. Troche
- Spine Pain Research Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Rachel L. Welch
- Spine Pain Research Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Beth A. Winkelstein
- Spine Pain Research Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Beth A. Winkelstein,
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11
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Wong C, Barkai O, Wang F, Thörn Pérez C, Lev S, Cai W, Tansley S, Yousefpour N, Hooshmandi M, Lister KC, Latif M, Cuello AC, Prager-Khoutorsky M, Mogil JS, Séguéla P, De Koninck Y, Ribeiro-da-Silva A, Binshtok AM, Khoutorsky A. mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation. J Clin Invest 2022; 132:152635. [PMID: 35579957 PMCID: PMC9337825 DOI: 10.1172/jci152635] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 05/13/2022] [Indexed: 11/29/2022] Open
Abstract
The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation–induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation–induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.
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Affiliation(s)
- Calvin Wong
- Department of Anesthesia, McGill University, Montreal, Canada
| | - Omer Barkai
- Department of Medical Neurobiology, The Hebrew University, Jerusalem, Israel
| | - Feng Wang
- Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Canada
| | | | - Shaya Lev
- Department of Medical Neurobiology, The Hebrew University, Jerusalem, Israel
| | - Weihua Cai
- Department of Anesthesia, McGill University, Montreal, Canada
| | - Shannon Tansley
- Department of Psychology, McGill University, Montreal, Canada
| | - Noosha Yousefpour
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
| | | | - Kevin C Lister
- Department of Anesthesia, McGill University, Montreal, Canada
| | - Mariam Latif
- Department of Anesthesia, McGill University, Montreal, Canada
| | - A Claudio Cuello
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
| | | | - Jeffrey S Mogil
- Department of Psychology, McGill University, Montreal, Canada
| | - Philippe Séguéla
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Yves De Koninck
- Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Canada
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12
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Senel C, Kizilay YO, Turan K, Ongun S, Tuzel E. Does total knee arthroplasty affect overactive bladder symptoms in female patients? Int Urogynecol J 2022; 33:939-945. [PMID: 35212786 DOI: 10.1007/s00192-022-05121-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
Abstract
INTRODUCTION AND HYPOTHESIS In the current study we hypothesized that total knee arthroplasty might improve the overactive bladder symptoms by providing pain relief and improving physical function. METHODS One hundred patients who underwent total knee arthroplasty were preoperatively evaluated for overactive bladder and 47 patients that met inclusion criteria were included in this study. All the patients included in the study were assessed both preoperatively and at the 3rd month postoperatively using the Overactive Bladder-Validated 8 (OAB-V8) questionnaire for overactive bladder symptoms, the Oxford Knee Score (OKS) for pain and physical function, and the International Physical Activity Questionnaire-Short Form (IPAQ-SF) for physical activity. RESULTS The mean age of the patients was 65.4 ± 7 (56-83) years. The OAB-V8, OKS and IPAQ-SF scores significantly improved at the 3rd month postoperatively compared with the initial assessment. All the OAB-V8 domains, namely, frequency, urgency, nocturia, and urgency urinary incontinence, significantly improved following total knee arthroplasty. CONCLUSIONS Our results showed that following total knee arthroplasty, overactive bladder questionnaire scores significantly improved at the 3rd month postoperatively.
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Affiliation(s)
- Cagdas Senel
- Department of Urology, Balikesir University School of Medicine, Balikesir, Turkey.
| | - Yusuf Onur Kizilay
- Department of Orthopedics and Traumatology, Atlas University School of Medicine, Istanbul, Turkey
| | - Kayhan Turan
- Department of Orthopedics and Traumatology, Atlas University School of Medicine, Istanbul, Turkey
| | - Sakir Ongun
- Department of Urology, Balikesir University School of Medicine, Balikesir, Turkey
| | - Emre Tuzel
- Department of Urology, Balikesir University School of Medicine, Balikesir, Turkey
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13
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A High Body Mass Index and the Vacuum Phenomenon Upregulate Pain-Related Molecules in Human Degenerated Intervertebral Discs. Int J Mol Sci 2022; 23:ijms23062973. [PMID: 35328395 PMCID: PMC8953228 DOI: 10.3390/ijms23062973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/05/2022] [Accepted: 03/09/2022] [Indexed: 01/02/2023] Open
Abstract
Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP’s pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (−) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (−) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP.
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14
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Li X, Xu Y, Li H, Jia L, Wang J, Liang S, Cai A, Tan X, Wang L, Wang X, Huang Y, Tao E, Ye H, Asakawa T. Verification of pain-related neuromodulation mechanisms of icariin in knee osteoarthritis. Biomed Pharmacother 2021; 144:112259. [PMID: 34607107 DOI: 10.1016/j.biopha.2021.112259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/19/2022] Open
Abstract
Knee osteoarthritis (KOA) is a common disease with no specific treatment. Icariin (ICA) is considered an agent for KOA. This study aimed to confirm the pain-related neuromodulation mechanisms of ICA on KOA. Three experiments were designed: (1) verifying the therapeutic effects of ICA in vivo and in vitro, (2) exploring the potential pain-related neuromodulation pathways involved in ICA treatment by functional magnetic resonance imaging (fMRI) and virus retrograde tracing (VRT) and (3) confirming the pain-related targets by tandem mass tag (TMT)-based quantitative proteomics and bioinformatic analyses. Experiment 1 verified the efficacy of ICA in OA animal and cell models. Experiment 2 found a series of brain regions associated with KOA reversed by ICA treatment, indicating that a pain-related hypothalamic-mediated neuromodulation pathway and an endocannabinoid (EC)-related pathway contribute to ICA mechanisms. Experiment 3 explored and confirmed four pain-related genes involved in KOA and ICA treatment. We confirmed the key role of pain-related neuromodulation mechanisms in ICA treatment associated with its analgesic effect. Our findings contribute to considering ICA as a novel therapy for KOA.
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MESH Headings
- Analgesics/pharmacology
- Animals
- Antirheumatic Agents/pharmacology
- Arthritis, Experimental/diagnostic imaging
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/physiopathology
- Behavior, Animal/drug effects
- Brain/diagnostic imaging
- Brain/drug effects
- Brain/metabolism
- Brain/physiopathology
- Cells, Cultured
- Chondrocytes/drug effects
- Chondrocytes/metabolism
- Flavonoids/pharmacology
- Gene Expression Regulation
- Inflammation Mediators/metabolism
- Joints/drug effects
- Joints/innervation
- Joints/metabolism
- Magnetic Resonance Imaging
- Male
- Mice, Inbred C57BL
- Neuroanatomical Tract-Tracing Techniques
- Neuropeptides/genetics
- Neuropeptides/metabolism
- Osteoarthritis, Knee/diagnostic imaging
- Osteoarthritis, Knee/drug therapy
- Osteoarthritis, Knee/metabolism
- Osteoarthritis, Knee/physiopathology
- Pain Threshold/drug effects
- Proteomics
- Rats, Sprague-Dawley
- Signal Transduction
- Tandem Mass Spectrometry
- Mice
- Rats
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Affiliation(s)
- Xihai Li
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China
| | - Yunteng Xu
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Hui Li
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Liangliang Jia
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Jie Wang
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan 430071, China; Innovation Academy for Precision Measurement Science, Wuhan 430071, China
| | - Shengxiang Liang
- National-Local Joint Engineering Research Center of Rehabilitation Medicine Technology, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Rehabilitation Industry Institute, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Aoling Cai
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan 430071, China; Innovation Academy for Precision Measurement Science, Wuhan 430071, China
| | - Xue Tan
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Lili Wang
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Xiaoning Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China
| | - Yanfeng Huang
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Enxiang Tao
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China
| | - Hongzhi Ye
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| | - Tetsuya Asakawa
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China; Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
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15
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Sinhorim L, Amorim MDS, Ortiz ME, Bittencourt EB, Bianco G, da Silva FC, Horewicz VV, Schleip R, Reed WR, Mazzardo-Martins L, Martins DF. Potential Nociceptive Role of the Thoracolumbar Fascia: A Scope Review Involving In Vivo and Ex Vivo Studies. J Clin Med 2021; 10:jcm10194342. [PMID: 34640360 PMCID: PMC8509394 DOI: 10.3390/jcm10194342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/09/2021] [Accepted: 09/20/2021] [Indexed: 12/23/2022] Open
Abstract
Nociceptive innervation of the thoracolumbar fascia (TLF) has been investigated over the past few decades; however, these studies have not been compiled or collectively appraised. The purpose of this scoping review was to assess current knowledge regarding nociceptive innervation of the TLF to better inform future mechanistic and clinical TLF research targeting lower back pain (LBP) treatment. PubMed, ScienceDirect, Cochrane, and Embase databases were searched in January 2021 using relevant descriptors encompassing fascia and pain. Eligible studies satisfied the following: (a) published in English; (b) preclinical and clinical (in vivo and ex vivo) studies; (c) original data; (d) included quantification of at least one TLF nociceptive component. Two-phase screening procedures were conducted by a pair of independent reviewers, after which data were extracted and summarized from eligible studies. The search resulted in 257 articles of which 10 met the inclusion criteria. Studies showed histological evidence of nociceptive nerve fibers terminating in lower back fascia, suggesting a TLF contribution to LBP. Noxious chemical injection or electrical stimulation into fascia resulted in longer pain duration and higher pain intensities than injections into subcutaneous tissue or muscle. Pre-clinical and clinical research provides histological and functional evidence of nociceptive innervation of TLF. Additional knowledge of fascial neurological components could impact LBP treatment.
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Affiliation(s)
- Larissa Sinhorim
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Palhoça 88137-272, Brazil
| | - Mayane dos Santos Amorim
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Human Movement Sciences Graduate Program, College of Health and Sport Science at Santa Catarina State University, Florianópolis 88080-350, Brazil
| | - Maria Eugênia Ortiz
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Palhoça 88137-272, Brazil
| | - Edsel Balduino Bittencourt
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Coastal Health Institute, Jacksonville, FL 32224, USA
| | - Gianluca Bianco
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Research Laboratory of Posturology and Neuromodulation RELPON, Department of Human Neuroscience, Sapienza University, 00147 Rome, Italy
- Istituto di Formazione in Agopuntura e Neuromodulazione IFAN, 00147 Roma, Italy
| | | | - Verônica Vargas Horewicz
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Palhoça 88137-272, Brazil
| | - Robert Schleip
- Department of Sport and Health Sciences, Technical University of Munich, 80799 Munich, Germany
- Department for Medical Professions, DIPLOMA University of Applied Sciences, 37242 Bad Sooden-Allendorf, Germany
- Correspondence: ; Tel.: +49-89-346016
| | - William R. Reed
- Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Rehabilitation Science Program, Departments of Physical and Occupational Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Leidiane Mazzardo-Martins
- Postgraduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil;
| | - Daniel F. Martins
- Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça 88137-272, Brazil; (L.S.); (M.d.S.A.); (M.E.O.); (E.B.B.); (G.B.); (V.V.H.); (D.F.M.)
- Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Palhoça 88137-272, Brazil
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16
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Maleitzke T, Hildebrandt A, Weber J, Dietrich T, Appelt J, Jahn D, Zocholl D, Baranowsky A, Duda GN, Tsitsilonis S, Keller J. Proinflammatory and bone protective role of calcitonin gene-related peptide alpha in collagen antibody-induced arthritis. Rheumatology (Oxford) 2021; 60:1996-2009. [PMID: 33221885 DOI: 10.1093/rheumatology/keaa711] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 09/22/2020] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling. METHODS Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT. RESULTS CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1β, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time. CONCLUSION This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.
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Affiliation(s)
- Tazio Maleitzke
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Alexander Hildebrandt
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jérôme Weber
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Tamara Dietrich
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jessika Appelt
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Denise Jahn
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dario Zocholl
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anke Baranowsky
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Georg N Duda
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Serafeim Tsitsilonis
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Johannes Keller
- Berlin Institute of Health (BIH), Berlin, Germany.,Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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17
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Grässel S, Zaucke F, Madry H. Osteoarthritis: Novel Molecular Mechanisms Increase Our Understanding of the Disease Pathology. J Clin Med 2021; 10:jcm10091938. [PMID: 33946429 PMCID: PMC8125020 DOI: 10.3390/jcm10091938] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Although osteoarthritis (OA) is the most common musculoskeletal condition that causes significant health and social problems worldwide, its exact etiology is still unclear. With an aging and increasingly obese population, OA is becoming even more prevalent than in previous decades. Up to 35% of the world’s population over 60 years of age suffers from symptomatic (painful, disabling) OA. The disease poses a tremendous economic burden on the health-care system and society for diagnosis, treatment, sick leave, rehabilitation, and early retirement. Most patients also experience sleep disturbances, reduced capability for exercising, lifting, and walking and are less capable of working, and maintaining an independent lifestyle. For patients, the major problem is disability, resulting from joint tissue destruction and pain. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Here, we elucidate novel concepts and hypotheses regarding disease progression and pathology, which are relevant for understanding underlying the molecular mechanisms as a prerequisite for future therapeutic approaches. Emphasis is placed on topographical modeling of the disease, the role of proteases and cytokines in OA, and the impact of the peripheral nervous system and its neuropeptides.
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Affiliation(s)
- Susanne Grässel
- Department of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB), Bio Park 1, University of Regensburg, 93053 Regensburg, Germany
- Correspondence:
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim, 60528 Frankfurt am Main, Germany;
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University, 66421 Homburg, Germany;
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18
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Meheux CJ, Hirase T, Dong D, Clyburn TA, Harris JD. Healthy Hip Joints Have Different Macroscopic and Microscopic Capsular Nerve Architecture Compared With Hips With Osteoarthritis, Femoroacetabular Impingement Syndrome, and Developmental Dysplasia of the Hip: A Systematic Review. Arthrosc Sports Med Rehabil 2021; 3:e269-e276. [PMID: 33615274 PMCID: PMC7879181 DOI: 10.1016/j.asmr.2020.08.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/10/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE To perform a systematic review to identify macroscopic and microscopic patterns and differences in hip capsule innervation between normal hips and hips with osteoarthritis (OA), femoroacetabular impingement (FAI) syndrome, and developmental dysplasia of the hip (DDH). METHODS A systematic review was performed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Multiple databases were searched for both clinical and basic science laboratory studies on hip capsule innervation. Non-innervation capsule and non-human animal studies were excluded. Macroscopic and microscopic differences in capsular innervation between normal hips, and hips with OA, FAI, and DDH were analyzed. Methodological quality assessment of all studies included in this review was completed using the Methodological Index for Non-randomized Studies. RESULTS Ten articles were analyzed (263 specimens; 211 patients, 52 cadavers; mean Methodological Index for Non-randomized Studies 10/16). The hip capsule is innervated by the sciatic and superior gluteal nerves posterosuperiorly, nerve to quadratus femoris and inferior gluteal nerve posteroinferiorly, and femoral and obturator nerves anteriorly. The anterior-superior capsule between 1:00 and 2:30 o'clock on a right hip is a safe internervous zone. The superolateral capsule has the greatest density of mechanoreceptors and sensory fibers. OA is associated with a greater expression of nerve fibers compared with normal hips but does not correlate with pain or disability. No significant differences were found in nerve fiber expression among patients with DDH, FAI, or normal hips. A negative correlation is seen with aging and pain fiber expression. CONCLUSIONS The hip capsule has a complex macroscopic and microscopic innervation pattern with varying nerve fiber expression from at least 6 separate peripheral nerves. OA is associated with a greater expression of nerve fibers, although nerve fiber expression does not correlate with painful pathology. LEVEL OF EVIDENCE IV, Systematic review of level I-IV studies.
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Affiliation(s)
- Carlos J. Meheux
- Houston Methodist Orthopedic and Sports Medicine, Houston, Texas, U.S.A
| | - Takashi Hirase
- Houston Methodist Orthopedic and Sports Medicine, Houston, Texas, U.S.A
| | - David Dong
- Houston Methodist Orthopedic and Sports Medicine, Houston, Texas, U.S.A
| | - Terry A. Clyburn
- Houston Methodist Orthopedic and Sports Medicine, Houston, Texas, U.S.A
| | - Joshua D. Harris
- Houston Methodist Orthopedic and Sports Medicine, Houston, Texas, U.S.A
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Abstract
As our understanding of hip function and disease improves, it is evident that the acetabular fossa has received little attention, despite it comprising over half of the acetabulum’s surface area and showing the first signs of degeneration. The fossa’s function is expected to be more than augmenting static stability with the ligamentum teres and being a templating landmark in arthroplasty. Indeed, the fossa, which is almost mature at 16 weeks of intrauterine development, plays a key role in hip development, enabling its nutrition through vascularization and synovial fluid, as well as the influx of chondrogenic stem/progenitor cells that build articular cartilage. The pulvinar, a fibrofatty tissue in the fossa, has the same developmental origin as the synovium and articular cartilage and is a biologically active area. Its unique anatomy allows for homogeneous distribution of the axial loads into the joint. It is composed of intra-articular adipose tissue (IAAT), which has adipocytes, fibroblasts, leucocytes, and abundant mast cells, which participate in the inflammatory cascade after an insult to the joint. Hence, the fossa and pulvinar should be considered in decision-making and surgical outcomes in hip preservation surgery, not only for their size, shape, and extent, but also for their biological capacity as a source of cytokines, immune cells, and chondrogenic stem cells. Cite this article: Bone Joint Res 2020;9(12):857–869.
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Affiliation(s)
- Pablo A Slullitel
- 'Sir John Charnley' Hip Surgery Unit, Institute of Orthopaedics 'Carlos E. Ottolenghi', Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Daniel Coutu
- Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada
| | - Martin A Buttaro
- 'Sir John Charnley' Hip Surgery Unit, Institute of Orthopaedics 'Carlos E. Ottolenghi', Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Paul Edgar Beaule
- Division of Orthopaedic Surgery, The Ottawa Hospital, Ottawa, Canada
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Lee SH, Choi HH, Chang MC. The Effect of Botulinum Toxin Injection into the Common Extensor Tendon in Patients with Chronic Lateral Epicondylitis: A Randomized Trial. PAIN MEDICINE (MALDEN, MASS.) 2020; 21:1971-1976. [PMID: 31804698 DOI: 10.1093/pm/pnz323] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Botulinum toxin (BTX) is widely used for pain control in various musculoskeletal disorders. OBJECTIVES We evaluated the analgesic effect of botulinum toxin type A (BTX-A) in chronic lateral epicondylitis and compared the effect between 10 and 50 IU of BTX-A. METHODS Sixty subjects with chronic lateral epicondylitis were included and underwent a BTX-A injection in the common extensor tendon. The subjects were randomly allocated into two groups: the small-dose group (SD group; 30 subjects, 10 IU) and large-dose group (LD group; 30 subjects, 50 IU). Treatment outcomes were evaluated by measuring the pain level using the numeric rating scale (NRS) and measuring grip strength before and one, two, three, four, five, and six months after treatment. RESULTS Subjects in both groups showed a significant decrease in NRS scores at all evaluation time points after treatment. The reduction in NRS scores was significantly greater in the LD group at one, two, three, and four months after treatment. Six months after treatment, 19 subjects (63.3%) in the SD group and 21 (70%) in the LD group reported successful pain relief (pain relief ≥50%). The rate of successful pain relief was not significantly different between the two groups. Grip strength was more increased in the LD group at one, two, three, four, and six months after treatment. CONCLUSIONS BTX-A injection into the common extensor tendon can be a good treatment option for chronic lateral epicondylitis. The 50-IU BTX-A injection achieved a better outcome than the 10-IU injection.
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Affiliation(s)
- Sang Hoon Lee
- Department of Radiology, Madi Pain Management Center, Jeonju, Republic of Korea
| | - Hyun Hee Choi
- Madi Research and Development Center, Jeonju, Republic of Korea
| | - Min Cheol Chang
- Department of Rehabilitation Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
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21
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Aso K, Shahtaheri SM, Hill R, Wilson D, McWilliams DF, Nwosu LN, Chapman V, Walsh DA. Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats. Osteoarthritis Cartilage 2020; 28:1245-1254. [PMID: 32470596 DOI: 10.1016/j.joca.2020.05.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Subchondral bone may contribute to knee osteoarthritis (OA) pain. Nerve growth factor (NGF) can stimulate nerve growth through TrkA. We aimed to identify how sensory nerve growth at the osteochondral junction in human and rat knees associates with OA pain. METHODS Eleven symptomatic chondropathy cases were selected from people undergoing total knee replacement for OA. Twelve asymptomatic chondropathy cases who had not presented with knee pain were selected post-mortem. OA was induced in rat knees by meniscal transection (MNX) and sham-operated rats were used as controls. Twice-daily oral doses (30 mg/kg) of TrkA inhibitor (AR786) or vehicle were administered from before and up to 28 days after OA induction. Joints were analysed for macroscopic appearances of articular surfaces, OA histopathology and calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerves in medial tibial plateaux, and rats were assessed for pain behaviors. RESULTS The percentage of osteochondral channels containing CGRP-IR nerves in symptomatic chondropathy was higher than in asymptomatic chondropathy (difference: 2.5% [95% CI: 1.1-3.7]), and in MNX-than in sham-operated rat knees (difference: 7.8% [95%CI: 1.7-15.0]). Osteochondral CGRP-IR innervation was significantly associated with pain behavior in rats. Treatment with AR786 prevented the increase in CGRP-IR nerves in osteochondral channels and reduced pain behavior in MNX-operated rats. Structural OA was not significantly affected by AR786 treatment. CONCLUSIONS CGRP-IR sensory nerves within osteochondral channels are associated with pain in human and rat knee OA. Reduced pathological innervation of the osteochondral junction might contribute to analgesic effects of reduced NGF activity achieved by blocking TrkA.
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Affiliation(s)
- K Aso
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK; Department of Orthopedic Surgery, Kochi Medical School, Kochi University, 185-1 Oko-cho Kohasu, Nankoku, 783-8505, Japan.
| | - S M Shahtaheri
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK
| | - R Hill
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK; Sherwood Forest Hospitals NHS Foundation Trust, Mansfield Road, Sutton in Ashfield, NG17 4JL, UK
| | - D Wilson
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK; Sherwood Forest Hospitals NHS Foundation Trust, Mansfield Road, Sutton in Ashfield, NG17 4JL, UK
| | - D F McWilliams
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK
| | - L N Nwosu
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, NE2 4HH, UK
| | - V Chapman
- Arthritis Research UK Pain Centre, School of Life Sciences, University of Nottingham, NG7 2UH, UK
| | - D A Walsh
- Arthritis Research UK Pain Centre & NIHR Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, NG5 1PB, UK; Sherwood Forest Hospitals NHS Foundation Trust, Mansfield Road, Sutton in Ashfield, NG17 4JL, UK
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Tomlinson J, Zwirner J, Ondruschka B, Prietzel T, Hammer N. Innervation of the hip joint capsular complex: A systematic review of histological and immunohistochemical studies and their clinical implications for contemporary treatment strategies in total hip arthroplasty. PLoS One 2020; 15:e0229128. [PMID: 32101545 PMCID: PMC7043757 DOI: 10.1371/journal.pone.0229128] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 01/30/2020] [Indexed: 01/17/2023] Open
Abstract
The hip joint capsule contributes to the stability of the hip joint and lower extremity, yet this structure is incised and often removed during total hip arthroplasty (THA). Increasing incidence of osteoarthritis is accompanied by a dramatic rise in THAs over the last few decades. Consequently, to improve this treatment, THA with capsular repair has evolved. This partial restoration of physiological hip stability has resulted in a substantial reduction in post-operative dislocation rates compared to conventional THA without capsular repair. A further reason for the success of this procedure is thought to be the preservation of the innervation of the capsule. A systematic review of studies investigating the innervation of the hip joint capsular complex and pseudocapsule with histological techniques was performed, as this is not well established. The literature was sought from databases Amed, Embase and Medline via OVID, PubMed, ScienceDirect, Scopus and Web of Science; excluding articles without a histological component and those involving animals. A total of 21 articles on the topic were identified. The literature indicates two primary outcomes and potential clinical implications of the innervation of the capsule. Firstly, a role in the mechanics of the hip joint, as mechanoreceptors may be present in the capsule. However, the nomenclature used to describe the distribution of the innervation is inconsistent. Furthermore, the current literature is unable to reliably confirm the proprioceptive role of the capsule, as no immunohistochemical study to date has reported type I-III mechanoreceptors in the capsule. Secondly, the capsule may play a role in pain perception, as the density of innervation appears to be altered in painful individuals. Also, increasing age may indicate requirements for different strategies to surgically manage the hip capsule. However, this requires further study, as well as the role of innervation according to sex, specific pathology and other morphometric variables. Increased understanding may highlight the requirement for capsular repair following THA, how this technique may be developed and the contribution of the capsule to joint function and stability.
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Affiliation(s)
- Joanna Tomlinson
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, Otago, New Zealand
| | - Johann Zwirner
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, Otago, New Zealand
| | - Benjamin Ondruschka
- Institute of Legal Medicine, Faculty of Medicine, University of Leipzig, Leipzig, Saxony, Germany
| | - Torsten Prietzel
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Zeisigwaldkliniken Bethanien, Chemnitz, Saxony, Germany
- Department of Orthopaedic, Trauma and Plastic Surgery, University of Leipzig, Leipzig, Saxony, Germany
| | - Niels Hammer
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, Otago, New Zealand
- Department of Orthopaedic, Trauma and Plastic Surgery, University of Leipzig, Leipzig, Saxony, Germany
- Division of Medical Technology, Fraunhofer Institute for Machine Tools and Forming Technology (Fraunhofer IWU), Dresden, Saxony, Germany
- Institute of Macroscopic and Clinical Anatomy, University of Graz, Graz, Styria, Austria
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23
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Sun S, Diggins NH, Gunderson ZJ, Fehrenbacher JC, White FA, Kacena MA. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone 2020; 131:115109. [PMID: 31715336 PMCID: PMC6934100 DOI: 10.1016/j.bone.2019.115109] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 12/30/2022]
Abstract
Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.
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Affiliation(s)
- Seungyup Sun
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Nicklaus H Diggins
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Zachary J Gunderson
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA
| | - Jill C Fehrenbacher
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, IN, USA
| | - Fletcher A White
- Department of Anesthesia, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, IN, USA; Richard L. Roudebush VA Medical Center, IN, USA.
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Rein S, Okogbaa J, Hagert E, Manthey S, Ladd A. Histopathological analysis of the synovium in trapeziometacarpal osteoarthritis. J Hand Surg Eur Vol 2019; 44:1079-1088. [PMID: 31109229 DOI: 10.1177/1753193419848600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Dorsoradial and anterior oblique ligaments were harvested during surgery in 13 patients with symptomatic trapeziometacarpal osteoarthritis, which had been graded preoperatively by a modified Eaton-Littler radiographic grading. Ligaments, including the periligamentous synovium, were stained with S100 protein, neurotrophic receptor p75, protein gene product 9.5, calcitonin gene related peptide, acetylcholine, substance P, neuropeptide Y, noradrenaline, N-methyl-D-aspartate-receptor and Met/Leu-enkephalin. The synovium was classified as showing no, low-grade or high-grade synovitis. Free nerve endings had higher immunoreactivity for substance P than for N-methyl-D-aspartate-receptor, enkephalin and noradrenaline. The synovial stroma had less immunoreactivity for N-methyl-D-aspartate-receptor than for noradrenaline, substance P and calcitonin gene related peptide. There was no relation between the grade of osteoarthritis and the visual pain analogue scale, synovitis score, immunoreactivity of all antibodies and quantity of free nerve endings or blood vessels. Synovium in trapeziometacarpal joint osteoarthritis produces several neuromediators causing a polymodal neurogenic inflammation and which may serve as biomarkers for osteoarthritis or therapeutic targets.
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Affiliation(s)
- Susanne Rein
- Department of Plastic and Hand Surgery, Burn Unit, Hospital Sankt Georg, Leipzig, Germany
| | - Janet Okogbaa
- Department of Orthopaedic Surgery, Chase Hand Center, Stanford University, Stanford, CA, USA
| | - Elisabet Hagert
- Department of Clinical Science and Education, Karolinska Institutet, Arcademy, H. M. Queen Sophia Hospital, Stockholm, Sweden
| | - Suzanne Manthey
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany
| | - Amy Ladd
- Department of Orthopaedic Surgery, Chase Hand Center, Stanford University, Stanford, CA, USA
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25
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de Sousa Valente J. The Pharmacology of Pain Associated With the Monoiodoacetate Model of Osteoarthritis. Front Pharmacol 2019; 10:974. [PMID: 31619987 PMCID: PMC6759799 DOI: 10.3389/fphar.2019.00974] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 07/31/2019] [Indexed: 12/31/2022] Open
Abstract
The high incidence of osteoarthritis (OA) in an increasingly elderly population anticipates a dramatic rise in the number of people suffering from this disease in the near future. Because pain is the main reason patients seek medical help, effective pain management-which is currently lacking-is paramount to improve the quality of life that OA sufferers desperately seek. Good animal models are, in this day and age, fundamental tools for basic research of new therapeutic pathways. Several animal models of OA have been characterized, but none of them reproduces entirely all symptoms of the disease. Choosing between different animal models depends largely on which aspect of OA one aims to study. Here, we review the current understanding of the monoiodoacetate (MIA) model of OA. MIA injection in the knee joint leads to the progressive disruption of cartilage, which, in turn, is associated with the development of pain-like behavior. There are several reasons why the MIA model of OA seems to be the most adequate to study the pharmacological effect of new drugs in pain associated with OA. First, the pathological changes induced by MIA share many common traits with those observed in human OA (Van Der Kraan et al., 1989; Guingamp et al., 1997; Guzman et al., 2003), including loss of cartilage and alterations in the subchondral bone. The model has been extensively utilized in basic research, which means that the time course of pain-related behaviors and histopathological changes, as well as pharmacological profile, namely of commonly used pain-reducing drugs, is now moderately understood. Also, the severity of the progression of pathological changes can be controlled by grading the concentration of MIA administered. Further, in contrast with other OA models, MIA offers a rapid induction of pain-related phenotypes, with the cost-saving consequence in new drug screening. This model, therefore, may be more predictive of clinical efficacy of novel pharmacological tools than other chronic or acute OA models.
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Affiliation(s)
- João de Sousa Valente
- Vascular Biology and Inflammation Section, Cardiovascular School of Medicine and Sciences, British Heart Foundation Centre of Excellence, King's College London, London, United Kingdom
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26
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Abstract
CGRP has long been suspected as a mediator of arthritis pain, although evidence that CGRP directly mediates human musculoskeletal pain remains circumstantial. This chapter describes in depth the evidence surrounding CGRP's association with pain in musculoskeletal disorders and also summarises evidence for CGRP being a direct cause of pain in other conditions. CGRP-immunoreactive nerves are present in musculoskeletal tissues, and CGRP expression is altered in musculoskeletal pain. CGRP modulates musculoskeletal pain through actions both in the periphery and central nervous system. Human observational studies, research on animal arthritis models and the few reported randomised controlled trials in humans of treatments that target CGRP provide the context of CGRP as a possible pain biomarker or mediator in conditions other than migraine.
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Affiliation(s)
- David A Walsh
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK.
- Rheumatology, Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, UK.
| | - Daniel F McWilliams
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK
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27
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Thudium CS, Löfvall H, Karsdal MA, Bay-Jensen AC, Bihlet AR. Protein biomarkers associated with pain mechanisms in osteoarthritis. J Proteomics 2019; 190:55-66. [DOI: 10.1016/j.jprot.2018.04.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 04/16/2018] [Accepted: 04/20/2018] [Indexed: 12/19/2022]
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28
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Liliana R, Slawomir G, Tomasz J, Joanna W, Andrzej P. The effects of Bisphenol A (BPA) on sympathetic nerve fibers in the uterine wall of the domestic pig. Reprod Toxicol 2018; 84:39-48. [PMID: 30562551 DOI: 10.1016/j.reprotox.2018.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/08/2018] [Accepted: 12/14/2018] [Indexed: 12/20/2022]
Abstract
Bisphenol A (BPA), used in the production of plastic, shows multidirectional negative effects on the living organism. BPA may affect the reproductive and nervous systems; however, its influence on the nerves supplying the uterus has not been studied. During the present study, the impact of BPA on the sympathetic nerves in the uterus was investigated using a double immunofluorescence technique. The results have shown that even low doses of BPA may change the neurochemical characterization of uterine sympathetic nerves, and the severity of these changes depends on the part of the uterus and the dose of the toxic substance. Probably the changes observed during the present study resulted from the neurotoxic and/or pro-inflammatory activity of BPA, but the exact mechanism for the observed fluctuation still remains unknown. The fluctuations of the neurochemical characterization of the uterine intramural nerves may be the first subclinical signs of harmful exposure to BPA.
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Affiliation(s)
- Rytel Liliana
- Department of Internal Disease with Clinic, Faculty of Veterinary Medicine, University of Warmia and Mazury, Poland.
| | - Gonkowski Slawomir
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Poland
| | - Janowski Tomasz
- Department of Animal Reproduction with Clinic, Faculty of Veterinary Medicine, University of Warmia and Mazury, Poland
| | - Wojtkiewicz Joanna
- Department of Pathophysiology, School of Medicine, University of Warmia and Mazury, Poland
| | - Pomianowski Andrzej
- Department of Internal Disease with Clinic, Faculty of Veterinary Medicine, University of Warmia and Mazury, Poland
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29
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Plasma Concentration of Norepinephrine, β-endorphin, and Substance P in Lame Dairy Cows. J Vet Res 2018; 62:193-197. [PMID: 30364907 PMCID: PMC6200290 DOI: 10.2478/jvetres-2018-0029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 06/13/2018] [Indexed: 12/28/2022] Open
Abstract
Introduction Lameness is a painful and debilitating condition that affects dairy cows worldwide. The aim of this study was to determine the plasma concentration of norepinephrine, β-endorphin, and substance P in dairy cows with lameness and different mobility scores (MS). Material and Methods A total of 100 Friesian and Jersey cows with lameness (parity range: 1-6; weight: 400-500 kg; milk yield: 22-28 L a day, and lactation stage less than 230 days) were selected. Animals were selected and grouped according to MS (MS 0-3; n = 25), and plasma concentration of norepinephrine, substance P, and β-endorphin was measured using ELISA. Results Cows with MS 3 had higher plasma concentrations of norepinephrine and substance P and lower plasma concentrations of β-endorphins when compared to MS 0 cows. Conclusion Variations in plasma concentration of norepinephrine, substance P, and β-endorphin could be associated with intense pain states in dairy cows with lameness, but are insufficient to differentiate these states from the mildest pain states. Further studies are necessary in order to evaluate the potential use of these biomarkers in the detection of chronic bovine painful conditions.
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30
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Pujol R, Girard CA, Richard H, Hassanpour I, Binette MP, Beauchamp G, McDougall JJ, Laverty S. Synovial nerve fiber density decreases with naturally-occurring osteoarthritis in horses. Osteoarthritis Cartilage 2018; 26:1379-1388. [PMID: 29958917 DOI: 10.1016/j.joca.2018.06.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 05/10/2018] [Accepted: 06/07/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To measure the nerve fiber density in synovial membranes from healthy and OA equine joints and to investigate the relationship between synovial innervation and OA severity, synovial vascularity and synovitis. DESIGN Twenty-five equine metacarpophalangeal joints were collected post-mortem. The joints were dissected and the macroscopic lesions of the articular cartilage were scored. Synovial membrane specimens (n = 50) were harvested, fixed, sectioned and scored histologically. Immunohistochemical staining and immunofluorescence with S-100 protein, that identifies nerve fibers, and ⍺-actin, that stains vascular smooth muscle, were also performed on site-matched specimens and the relationships between these tissues was interrogated. RESULTS The nerve fiber density was higher in the superficial layer (≤200 μm) of the synovium when compared to the deeper layer in control equine joints (mean difference (95% C.I.): 0.054% (0.018%, 0.11%)). In osteoarthritic joints, synovial innervation decreased in the superficial layer with increasing macroscopic OA score (β (SEM), 95% C.I.: -0.0061 (0.00021), -0.0011, -0.00017). The blood vessel density was also higher in the superficial layer of the synovium compared to the deep layer in the control (mean difference (95% C.I.): 1.1% (0.36%, 2.3%)) and OA (mean difference (95% C.I.): 0.60% (0.22%, 1.2%)) equine joints. Moreover, considering all synovial specimens, higher nerve fiber density in the deep layer positively correlated with blood vessel density (β (SEM), 95% C.I.: 0.11 (0.036), 0.035, 0.18). CONCLUSION The reduction in nerve fiber density with advanced cartilage degeneration suggests that peripheral neuropathy is associated with equine OA. Whether this link is associated with neuropathic pain, requires further investigation.
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Affiliation(s)
- R Pujol
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - C A Girard
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - H Richard
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - I Hassanpour
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - M P Binette
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - G Beauchamp
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada
| | - J J McDougall
- Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada; Department of Anesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada
| | - S Laverty
- Comparative Orthopedic Research Laboratory, Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 7C6, Canada.
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Aikawa J, Uchida K, Takano S, Inoue G, Iwase D, Miyagi M, Mukai M, Shoji S, Sekiguchi H, Takaso M. Regulation of calcitonin gene-related peptide expression through the COX-2/mPGES-1/PGE2 pathway in the infrapatellar fat pad in knee osteoarthritis. Lipids Health Dis 2018; 17:215. [PMID: 30205824 PMCID: PMC6134514 DOI: 10.1186/s12944-018-0864-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 09/04/2018] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The infrapatellar fat pad (IFP) is implicated in knee osteoarthritis (KOA). Calcitonin gene-related peptide (CGRP), a vasoactive neuropeptide expressed in joint tissues and synovial tissues (ST), was recently found to be associated with KOA progression and pain. CGRP is expressed in the IFPs of human KOA patients; however, its regulation has not been elucidated. METHODS IFPs and STs were harvested from 138 KOA patients during total knee replacement (TKR) and analyzed for CGRP, cycloxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) expression using real-time polymerase chain reaction (PCR). To investigate CGRP regulation by prostaglandin E2 (PGE2), adipocytes (Ad) and the stromal vascular fraction (SVF) were harvested from IFPs using collagenase. Synovial cells (SYC) were also harvested from ST and stimulated with vehicle (serum-free culture medium), PGE2, or CGRP. RESULTS CGRP, COX-2, and mPGES-1 expression levels were significantly higher in IFPs than STs. PGE2 stimulation increased CGRP expression in Ad, the SVF, and SYC; however, CGRP expression was significantly higher in PGE2-stimulated SVF than PGE2-stimulated SYC. CGRP stimulation had no effect on COX-2 or mPGES-1 expression. CONCLUSIONS CGRP expression in the IFP of KOA patients is regulated by the COX-2/mPGES-1/PGE2 pathway.
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Affiliation(s)
- Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Dai Iwase
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Manabu Mukai
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Shintaro Shoji
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Hiroyuki Sekiguchi
- Shonan University of Medical Sciences Research Institute, Nishikubo 500, Chigasaki City, Kanagawa, 253-0083, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
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Shmagel A, Onizuka N, Langsetmo L, Vo T, Foley R, Ensrud K, Valen P. Low magnesium intake is associated with increased knee pain in subjects with radiographic knee osteoarthritis: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2018; 26:651-658. [PMID: 29454594 DOI: 10.1016/j.joca.2018.02.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 02/04/2018] [Accepted: 02/07/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE As magnesium mediates bone and muscle metabolism, inflammation, and pain signaling, we aimed to evaluate whether magnesium intake is associated with knee pain and function in radiographic knee osteoarthritis (OA). METHODS We investigated the associations between knee pain/function metrics and magnesium intake from food and supplements in 2548 Osteoarthritis Initiative cohort participants with prevalent radiographic knee OA (Kellgren-Lawrence score ≥2). Magnesium intake was assessed by Food Frequency Questionnaire (FFQ) at baseline. WOMAC and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores were reported annually with total follow up of 48 months. Analyses used linear mixed models. RESULTS Among participants with baseline radiographic knee OA the mean total magnesium intake was 309.9 mg/day (SD 132.6) for men, and 287.9 mg/day (SD 118.1) for women, with 68% of men and 44% of women below the estimated average requirement. Subjects with lower magnesium intake had worse knee OA pain and function scores, throughout the 48 months (P < 0.001). After adjustment for age, sex, race, body mass index (BMI), calorie intake, fiber intake, pain medication use, physical activity, renal insufficiency, smoking, and alcohol use, lower magnesium intake remained associated with worse pain and function outcomes (1.4 points higher WOMAC and 1.5 points lower KOOS scores for every 50 mg of daily magnesium intake, P < 0.05). Fiber intake was an effect modifier (P for interaction <0.05). The association between magnesium intake and knee pain and function scores was strongest among subjects with low fiber intake. CONCLUSION Lower magnesium intake was associated with worse pain and function in knee OA, especially among individuals with low fiber intake.
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Affiliation(s)
- A Shmagel
- Division of Rheumatic and Autoimmune Diseases, University of Minnesota, USA.
| | | | - L Langsetmo
- Minneapolis VA Center for Chronic Disease Outcomes Research, Department of Epidemiology and Community Health, School of Public Health, University of Minnesota, USA
| | - T Vo
- Department of Epidemiology and Community Health, School of Public Health, University of Minnesota, USA
| | - R Foley
- University of Minnesota, Division of Renal Diseases and Hypertension, USA
| | - K Ensrud
- University of Minnesota, Minneapolis VA Center for Chronic Disease Outcomes Research, USA
| | - P Valen
- University of Minnesota, Minneapolis VA Medical Center, USA
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Sienkiewicz W, Dudek A, Czaja K, Janeczek M, Chrószcz A, Kaleczyc J. Efficacy of lateral- versus medial-approach hip joint capsule denervation as surgical treatments of the hip joint pain; a neuronal tract tracing study in the sheep. PLoS One 2018; 13:e0190052. [PMID: 29329303 PMCID: PMC5766125 DOI: 10.1371/journal.pone.0190052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 12/07/2017] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To evaluate efficacy of denervation of the of the hip joint capsule (HJC), as a treatment of hip joint pain. Specifically, we tested the hypothesis that HJC denervation will significantly reduce the number of sensory neurons innervating the capsule. STUDY DESIGN Denervation of the HJC from a medial or lateral approach was followed by retrograde tracing of sensory neurons innervating the capsule. ANIMALS Twenty adult male sheep (30-40 kg of body weight; Polish merino breed) were used in the study. METHODS The hip joint was denervated from medial (n = 5) or lateral (n = 5) surgical approaches. Immediately after denervation, the retrograde neural tract tracer Fast Blue (FB) was injected into the HJC. An additional ten animals (n = 5 for medial and n = 5 for lateral approach) received the same treatment without HJC denervation to provide the appropriate controls. RESULTS Results of the study revealed that the vast majority of retrogradely labelled sensory neurons innervating the HJC originate from fifth lumbar to second sacral dorsal root ganglia. Both the medial and the lateral denervations significantly reduced the number of sensory neurons innervating the HJC (39.2% and 69.0% reduction respectively). CONCLUSIONS These results show that denervation of the HJC is an effective surgical procedure for reduction of the sensory neuronal input to the HJC. Moreover, the lateral approach was found to be significantly more effective for reducing sensory innervation as compared to the medial one.
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Affiliation(s)
- Waldemar Sienkiewicz
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
- * E-mail: (WS); (KC)
| | - Agnieszka Dudek
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Krzysztof Czaja
- Veterinary Biosciences & Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
- * E-mail: (WS); (KC)
| | - Maciej Janeczek
- Department of Animal Anatomy, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wrocław, Poland
| | - Aleksander Chrószcz
- Department of Animal Anatomy, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wrocław, Poland
| | - Jerzy Kaleczyc
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
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Sousa-Valente J, Calvo L, Vacca V, Simeoli R, Arévalo JC, Malcangio M. Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. Osteoarthritis Cartilage 2018; 26:84-94. [PMID: 28844566 DOI: 10.1016/j.joca.2017.08.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 08/10/2017] [Accepted: 08/17/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Aiming to delineate novel neuro-immune mechanisms for NGF/TrkA signalling in osteoarthritis (OA) pain, we evaluated inflammatory changes in the knee joints following injection of monoiodoacetate (MIA) in mice carrying a TrkA receptor mutation (P782S; TrkA KI mice). METHOD In behavioural studies we monitored mechanical hypersensitivity following intra-articular MIA and oral prostaglandin D2 (PGD2) synthase inhibitor treatments. In immunohistochemical studies we quantified joint mast cell numbers, calcitonin gene-related peptide expression in synovia and dorsal root ganglia, spinal cord neuron activation and microgliosis. We quantified joint leukocyte infiltration by flow cytometry analysis, and PGD2 generation and cyclooxygenase-2 (COX-2) expression in mast cell lines by ELISA and Western blot. RESULTS In TrkA KI mice we observed rapid development of mechanical hypersensitivity and amplification of dorsal horn neurons and microglia activation 7 days after MIA. In TrkA KI knee joints we detected significant leukocyte infiltration and mast cells located in the vicinity of synovial nociceptive fibres. We demonstrated that mast cells exposure to NGF results in up-regulation of COX-2 and increase of PGD2 production. Finally, we observed that a PGD2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI, at doses which were ineffective in wild type (WT) mice. CONCLUSION Using the TrkA KI mouse model, we delineated a novel neuro-immune pathway and suggest that NGF-induced production of PGD2 in joint mast cells is critical for referred mechanical hypersensitivity in OA, probably through the activation of PGD2 receptor 1 in nociceptors: TrkA blockade in mast cells constitutes a potential target for OA pain.
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Affiliation(s)
| | - L Calvo
- Department of Cell Biology and Pathology, Institute of Neurosciences Castilla y León, University of Salamanca, Salamanca, 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca, 37007, Spain.
| | - V Vacca
- Wolfson CARD, King's College London, SE1 1UL, UK; Institute of Cell Biology and Neurobiology, National Research Council, IRCCS Fondazione Santa Lucia, Rome, 00143, Italy.
| | - R Simeoli
- Wolfson CARD, King's College London, SE1 1UL, UK.
| | - J C Arévalo
- Department of Cell Biology and Pathology, Institute of Neurosciences Castilla y León, University of Salamanca, Salamanca, 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca, 37007, Spain.
| | - M Malcangio
- Wolfson CARD, King's College London, SE1 1UL, UK.
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Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain 2017; 18:34. [PMID: 28303458 PMCID: PMC5355411 DOI: 10.1186/s10194-017-0741-2] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 02/28/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Calcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been clarified. METHODS We performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials. RESULTS The literature search identified 375 citations of which 50 contained relevant original data. An association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain was found. In 13 out of 20 studies in somatic pain conditions, CGRP levels had a positive correlation with pain. Increased CGRP levels were reported in plasma, synovial and cerebrospinal fluid in subjects with musculoskeletal pain. A randomized clinical trial on monoclonal antibody, which selectively binds to and inhibits the activity of CGRP (galcanezumab) in patients with osteoarthritis knee pain, failed to demonstrate improvement of pain compared with placebo. No studies to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions. CONCLUSION The present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act as a neuromodulator in non-headache pain conditions. However, more studies are needed to fully understand the role of CGRP in nociceptive processing and therapy of chronic pain.
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Affiliation(s)
- Wendy Sophie Schou
- Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark
| | - Sait Ashina
- Department of Neurology, NYU Lutheran Headache Center, New York University School of Medicine, NYU Langone Medical Center, New York, NY, USA
| | - Faisal Mohammad Amin
- Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark
| | - Peter J Goadsby
- Basic & Clinical Neuroscience, and NIHR-Wellcome Trust King's Clinical Research Facility, King's College London, London, UK
| | - Messoud Ashina
- Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark.
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Courties A, Sellam J, Berenbaum F. Role of the autonomic nervous system in osteoarthritis. Best Pract Res Clin Rheumatol 2017; 31:661-675. [DOI: 10.1016/j.berh.2018.04.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/11/2018] [Indexed: 01/15/2023]
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da Silva MR, Linhares D, Vasconcelos DM, Alves CJ, Neves N, Costa G, Lamghari M. Neuroimmune expression in hip osteoarthritis: a systematic review. BMC Musculoskelet Disord 2017; 18:394. [PMID: 28893229 PMCID: PMC5594449 DOI: 10.1186/s12891-017-1755-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/07/2017] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Neuroimmune axis is central in the physiopathology of hip osteoarthritis (OA), but its specific pathways are still unclear. This systematic review aims to assess the nervous and immune system profile of patients with hip osteoarthritis (OA) when compared to healthy controls. METHODS A systematic review followed PRISMA guidelines was conducted. A two-step selection process was completed, and from 609 references 17 were included. The inclusion criteria were: original articles on adult patients with hip OA, with assessment of neuroimmune expression. Articles with other interventions prior to analysis and those without a control group were excluded. RESULTS Thirty-nine relevant neuroimmune markers were identified, with assessments in bone, cartilage, synovial membrane, synovial fluid, whole blood, serum and/or immune cells. GM-CSF, IFN-γ, IL-1α, IL-6, IL-8, IL-1 and TNF-α presented variable expression among tissues studied when compared between hip OA and controls. VEGFs and TGF-ß isoforms showed similar tendencies among tissues and studies. On nervous expression, CGRP, Tuj-1 and SP were increased in synovial membrane. Overall, patients with hip OA presented a higher number of overexpressed markers. CONCLUSIONS For the first time a systematic review on neuroimmune expression in patients with hip OA found an upregulation of neuroimmune markers, with deregulated balance between pro and anti-inflammatory cytokines. However, no clear systematic pattern was found, and few information is available on nervous expression. This highlights the importance of future research with clear methodologies to guide the management of these patients.
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Affiliation(s)
- Manuel Ribeiro da Silva
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal. .,INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal. .,Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal. .,Faculdade de Medicina, Universidade do Porto, Porto, Portugal. .,Orthopedic Department, CHSJ - Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.
| | - Daniela Linhares
- Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal.,Orthopedic Department, CHSJ - Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,MEDCIDS - Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Daniel Marques Vasconcelos
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Cecilia Juliana Alves
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Nuno Neves
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal.,Faculdade de Medicina, Universidade do Porto, Porto, Portugal.,Orthopedic Department, CHSJ - Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Gilberto Costa
- Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal.,Faculdade de Medicina, Universidade do Porto, Porto, Portugal.,Orthopedic Department, CHSJ - Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Meriem Lamghari
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Takano S, Uchida K, Inoue G, Minatani A, Miyagi M, Aikawa J, Iwase D, Onuma K, Mukai M, Takaso M. Increase and regulation of synovial calcitonin gene-related peptide expression in patients with painful knee osteoarthritis. J Pain Res 2017; 10:1099-1104. [PMID: 28546767 PMCID: PMC5436753 DOI: 10.2147/jpr.s135939] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Recent studies suggest that the vasodilatory neuropeptide calcitonin gene-related peptide (CGRP) is localized in the synovial tissue and may be involved in the pathology of hip and knee osteoarthritis (OA). However, the regulation and relationship between pain and CGRP expression levels in the synovial tissue of human OA patients are not fully understood. Methods Synovial tissues were harvested from 74 participants with radiographic knee OA (unilateral Kellgren/Lawrence grades 3–4) during total knee arthroplasty. CGRP-expressing cells in the resected tissue were identified by immunohistochemical analyses. To examine CGRP expression levels, CD14-positive (CD14+) (macrophage-rich cell fraction) and CD14-negative (CD14−; fibroblast-rich cell fraction) cells were isolated from the synovial tissue. To investigate the involvement of prostaglandin E2 (PGE2) in the regulation of CGRP expression, cultured CD14− and CD14+ cells were stimulated with PGE2. In addition, CGRP expression levels in the synovial tissue of OA patients with strong/severe (visual analog scale [VAS]≥6) and mild/moderate pain (VAS<6) were compared. Results CGRP-positive cells were detected in the intimal lining layer and comprised both CD14− and CD14+ cells. CGRP expression in non-cultured CD14− fractions was significantly higher than that in CD14+ fractions. The expression levels of CGRP were significantly increased in cultured CD14− cell fractions treated with exogenous PGE2, compared to untreated CD14− cell fractions. In contrast, treatment with PGE2 did not increase CGRP regardless of whether or not CD14+ cells expressed CGRP. Furthermore, CGRP expression in the VAS≥6 group was also significantly higher than that in the VAS<6 group. Conclusion These findings suggest that CGRP expression in the synovial fibroblasts is regulated by the COX-2/PGE2 pathway and that elevation of synovial CGRP levels may contribute to OA pain.
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Affiliation(s)
- Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Atsushi Minatani
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Dai Iwase
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kenji Onuma
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Manabu Mukai
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan
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Grässel S, Muschter D. Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology. Int J Mol Sci 2017; 18:ijms18050931. [PMID: 28452955 PMCID: PMC5454844 DOI: 10.3390/ijms18050931] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 12/21/2022] Open
Abstract
The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.
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Affiliation(s)
- Susanne Grässel
- Department of Orthopedic Surgery, Exp. Orthopedics, ZMB/Biopark 1, University of Regensburg, 93053 Regensburg, Germany.
| | - Dominique Muschter
- Department of Orthopedic Surgery, Exp. Orthopedics, ZMB/Biopark 1, University of Regensburg, 93053 Regensburg, Germany.
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Aikawa J, Uchida K, Takano S, Inoue G, Minatani A, Miyagi M, Iwase D, Sekiguchi H, Mukai M, Takaso M. Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patients. J Orthop Surg Res 2017; 12:65. [PMID: 28431586 PMCID: PMC5399802 DOI: 10.1186/s13018-017-0568-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 04/13/2017] [Indexed: 11/23/2022] Open
Abstract
Background The infrapatellar fat pad (IPFP) has been implicated as a possible source of osteoarthritis (OA) development and knee pain due to the production of inflammatory mediators and the existence of nerve fibers within this structure. Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that is localized to joint tissues and has recently been implicated in the development of knee OA and OA pain. To date, however, the expression levels of CGRP in the IPFP of human knee OA patients have not been examined. Methods IFFP and synovial (SYN) tissues were harvested from 100 individuals with radiographic knee OA (unilateral Kellgren/Lawrence [K/L] grades 2–4) during total knee arthroplasty and subjected to immunohistochemical analysis for CGRP localization. In addition, the messenger RNA (mRNA) expression levels of CGRP and cyclooxygenase-2 (COX-2) in the collected tissues were evaluated and compared using real-time PCR analysis of total RNA extracts. CGRP and COX-2 mRNA expression were also compared among individuals with K/L grades 2–4. Results CGRP-positive cells were detected in the capillaries within the IPFP and lining layer of SYN tissue. The expression levels of CGRP in the IPFP were positively correlated with COX-2 and were significantly higher than those in SYN tissue. CGRP expression in tissue from the KL4 group was twofold higher than that from the KL2 group. Conclusions The IPFP of knee OA patients produces relatively high levels of CGRP, which may be regulated by COX-2 at the transcriptional level. Further studies are needed to determine if CGRP levels are directly linked to OA pathology.
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Affiliation(s)
- Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan.
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Atsushi Minatani
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Dai Iwase
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Hiroyuki Sekiguchi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Manabu Mukai
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara, Kanagawa, 252-0374, Japan
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The effect of intra-articular botulinum toxin A on substance P, prostaglandin E 2, and tumor necrosis factor alpha in the canine osteoarthritic joint. BMC Vet Res 2017; 13:74. [PMID: 28327134 PMCID: PMC5359943 DOI: 10.1186/s12917-017-0990-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 03/08/2017] [Indexed: 11/27/2022] Open
Abstract
Background Recently, intra-articular botulinum toxin A (IA BoNT A) has been shown to reduce joint pain in osteoarthritic dogs. Similar results have been reported in human patients with arthritis. However, the mechanism of the antinociceptive action of IA BoNT A is currently not known. The aim of this study was to explore this mechanism of action by investigating the effect of IA BoNT A on synovial fluid (SF) and serum substance P (SP), prostaglandin E2 (PGE2), and tumor necrosis factor alpha (TNF-α) in osteoarthritic dogs. Additionally, the aim was to compare SF SP and PGE2 between osteoarthritic and non-osteoarthritic joints, and investigate associations between SP, PGE2, osteoarthritic pain, and the signalment of dogs. Thirty-five dogs with chronic naturally occurring osteoarthritis and 13 non-osteoarthritic control dogs were included in the study. Osteoarthritic dogs received either IA BoNT A (n = 19) or IA placebo (n = 16). Serum and SF samples were collected and osteoarthritic pain was evaluated before (baseline) and 2 and 8 weeks after treatment. Osteoarthritic pain was assessed with force platform, Helsinki Chronic Pain Index, and joint palpation. Synovial fluid samples were obtained from control dogs after euthanasia. The change from baseline in SP and PGE2 concentration was compared between the IA BoNT A and placebo groups. The synovial fluid SP and PGE2 concentration was compared between osteoarthritic and control joints. Associations between SP, PGE2, osteoarthritic pain, and the signalment of dogs were evaluated. Results There was no significant change from baseline in SP or PGE2 after IA BoNT A. Synovial fluid PGE2 was significantly higher in osteoarthritic compared to control joints. Synovial fluid PGE2 correlated with osteoarthritic pain. No associations were found between SP or PGE2 and the signalment of dogs. The concentration of TNF-α remained under the detection limit of the assay in all samples. Conclusions The results suggest that the antinociceptive effect of IA BoNT A in the joint might not be related to the inhibition of SP nor PGE2. Synovial fluid PGE2, but not SP, could be a marker for chronic osteoarthritis and pain in dogs.
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Yoo J, Yeo ED, Lee YK. Treatment of Osteochondral Lesions of the Talus in Athletes. ACTA ACUST UNITED AC 2017. [DOI: 10.5763/kjsm.2017.35.2.77] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Jungwoo Yoo
- Department of Orthopedics, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Eui Dong Yeo
- Department of Orthopedics, Veterans Health Service Medical Center, Seoul, Korea
| | - Young Koo Lee
- Department of Orthopedics, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
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Neuerburg C, Loer T, Mittlmeier L, Polan C, Farkas Z, Holdt LM, Utzschneider S, Schwiesau J, Grupp TM, Böcker W, Aszodi A, Wedemeyer C, Kammerlander C. Impact of vitamin E-blended UHMWPE wear particles on the osseous microenvironment in polyethylene particle-induced osteolysis. Int J Mol Med 2016; 38:1652-1660. [PMID: 27779642 PMCID: PMC5117748 DOI: 10.3892/ijmm.2016.2780] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/23/2016] [Indexed: 12/29/2022] Open
Abstract
Aseptic loosening mediated by wear particle-induced osteolysis (PIO) remains the major cause of implant loosening in endoprosthetic surgery. The development of new vitamin E (α-tocopherol)-blended ultra-high molecular weight polyethylene (VE-UHMWPE) with increased oxidation resistance and improved mechanical properties has raised hopes. Furthermore, regenerative approaches may be opened, as vitamin E supplementation has shown neuroprotective characteristics mediated via calcitonin gene-related peptide (CGRP), which is known to affect bone remodeling in PIO. Therefore, the present study aimed to further clarify the impact of VE-UHMWPE wear particles on the osseous microenvironment and to identify the potential modulatory pathways involved. Using an established murine calvaria model, mice were subjected to sham operation (SHAM group), or treated with UHMWPE or VE-UHMWPE particles for different experimental durations (7, 14 and 28 days; n=6/group). Morphometric analysis by micro-computed tomography detected significant (p<0.01) and comparable signs of PIO in all particle-treated groups, whereas markers of inflammation [tumor necrosis factor (TNF)-α/tartrate resistant acid phosphatase (TRAP) staining] and bone remodeling [Dickkopf-related protein 1 (DKK-1)/osteoprotegerin (OPG)] were most affected in the early stages following surgery. Taking the present data into account, VE-UHMWPE appears to have a promising biocompatibility and increased ageing resistance. According to the α-CGRP serum levels and immunohistochemistry, the impact of vitamin E on neuropeptidergic signaling and its chance for regenerative approaches requires further investigation.
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Affiliation(s)
- Carl Neuerburg
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
| | - Theresa Loer
- Department of Orthopedics and Trauma Surgery, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Lena Mittlmeier
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
| | - Christina Polan
- Department of Orthopedics and Trauma Surgery, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Zsuzsanna Farkas
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
| | - Lesca Miriam Holdt
- Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Sandra Utzschneider
- Department of Orthopaedic Surgery, Physical Medicine and Rehabilitation, Munich University Hospital LMU, Munich, Germany
| | - Jens Schwiesau
- Department of Orthopaedic Surgery, Physical Medicine and Rehabilitation, Munich University Hospital LMU, Munich, Germany
| | - Thomas M Grupp
- Department of Orthopaedic Surgery, Physical Medicine and Rehabilitation, Munich University Hospital LMU, Munich, Germany
| | - Wolfgang Böcker
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
| | - Attila Aszodi
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
| | - Christian Wedemeyer
- KKEL St. Barbara Hospital, Department of Orthopedics and Trauma Surgery, Gladbeck, Germany
| | - Christian Kammerlander
- Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Munich, Germany
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Minatani A, Uchida K, Inoue G, Takano S, Aikawa J, Miyagi M, Fujimaki H, Iwase D, Onuma K, Matsumoto T, Takaso M. Activation of calcitonin gene-related peptide signaling through the prostaglandin E2-EP1/EP2/EP4 receptor pathway in synovium of knee osteoarthritis patients. J Orthop Surg Res 2016; 11:117. [PMID: 27751171 PMCID: PMC5067902 DOI: 10.1186/s13018-016-0460-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/28/2016] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Calcitonin gene-related peptide (CGRP) is a 37-amino-acid vasodilatory neuropeptide that binds to receptor activity-modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CLR). Clinical and preclinical evidence suggests that CGRP is associated with hip and knee joint pain; however, the regulation mechanisms of CGRP/CGRP receptor signaling in synovial tissue are not fully understood. METHODS Synovial tissues were harvested from 43 participants with radiographic knee osteoarthritis (OA; unilateral Kellgren/Lawrence (K/L) grades 3-4) during total knee arthroplasty. Correlationships between the mRNA expression levels of CGRP and those of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and cycloxygenase-2 (COX-2) were evaluated using real-time PCR analysis of total RNA extracted from the collected synovial tissues. To investigate the factors controlling the regulation of CGRP and CGRP receptor expression, cultured synovial cells were stimulated with TNF-α, IL-1β, IL-6, and prostaglandin E2 (PGE2) and were also treated with PGE2 receptor (EP) agonist. RESULTS CGRP and COX-2 localized in the synovial lining layer. Expression of COX-2 positively correlated with CGRP mRNA expression in the synovial tissue of OA patients. The gene expression of CGRP and RAMP1 increased significantly in synovial cells exogenously treated with PGE2 compared to untreated control cells. In cultured synovial cells, CGRP gene expression increased significantly following EP4 agonist treatment, whereas RAMP1 gene expression increased significantly in the presence of exogenously added EP1 and EP2 agonists. CONCLUSIONS PGE2 appears to regulate CGRP/CGRP receptor signaling through the EP receptor in the synovium of knee OA patients.
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Affiliation(s)
- Atsushi Minatani
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Hisako Fujimaki
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Dai Iwase
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Kenji Onuma
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Toshihide Matsumoto
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
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Dudek A, Sienkiewicz W, Chrószcz A, Janeczek M, Kaleczyc J. Chemical Coding of Sensory Neurons Supplying the Hip Joint Capsule in the Sheep. Anat Histol Embryol 2016; 46:121-131. [PMID: 27353745 DOI: 10.1111/ahe.12241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 06/03/2016] [Indexed: 12/28/2022]
Abstract
Immunohistochemical properties of nerve fibres supplying the joint capsule were previously described in many mammalian species, but the localization of sensory neurons supplying this structure was studied only in laboratory animals, the rat and rabbit. However, there is no comprehensive data on the chemical coding of sensory neurons projecting to the hip joint capsule (HJC). The aim of this study was to establish immunohistochemical properties of sensory neurons supplying HJC in the sheep. The study was carried out on 10 sheep, weighing about 30-40 kg. The animals were injected with a retrograde neural tracer Fast Blue (FB) into HJC. Sections of the spinal ganglia (SpG) with FB-positive (FB+) neurons were stained using antibodies against calcitonin gene-related peptide (CGRP) substance P (SP), pituitary adenylate cyclase-activating peptide (PACAP), nitric oxide synthase (n-NOS), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), Leu-5-enkephalin (Leu-Enk), galanin (GAL) and vesicular acetylcholine transporter (VACHT). The vast majority of FB+ neurons supplying HJC was found in the ganglia from the 5th lumbar to the 2nd sacral. Immunohistochemistry revealed that most of these neurons were immunoreactive to CGRP or SP (80.7 ± 8.0% or 56.4 ± 4.8%, respectively) and many of them stained for PACAP or GAL (52.9 ± 2.9% or 50.6 ± 19.7%, respectively). Other populations of FB+ neurons were those immunoreactive to n-NOS (37.8 ± 9.7%), NPY (34.6 ± 6.7%), VIP (28.7 ± 4.8%), Leu-Enk (27.1 ± 14.6) and VACHT (16.7 ± 9.6).
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Affiliation(s)
- A Dudek
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-719, Olsztyn, Poland
| | - W Sienkiewicz
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-719, Olsztyn, Poland
| | - A Chrószcz
- Department of Animal Anatomy, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Kozuchowska 1/3, 51-631, Wrocław, Poland
| | - M Janeczek
- Department of Animal Anatomy, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Kozuchowska 1/3, 51-631, Wrocław, Poland
| | - J Kaleczyc
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-719, Olsztyn, Poland
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Fernandes ES, Russell FA, Alawi KM, Sand C, Liang L, Salamon R, Bodkin JV, Aubdool AA, Arno M, Gentry C, Smillie SJ, Bevan S, Keeble JE, Malcangio M, Brain SD. Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner. Arthritis Res Ther 2016; 18:7. [PMID: 26754745 PMCID: PMC4718045 DOI: 10.1186/s13075-015-0905-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 12/22/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor. METHODS Mono-arthritis was induced by unilateral intra-articular injection of complete Freund's adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 °C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full-field laser perfusion imager (FLPI) and using clearance of (99m)Technetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC-030031), substance P neurokinin 1 (NK1) receptors (SR140333) or calcitonin gene-related peptide (CGRP) (CGRP8-37). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples. RESULTS Cold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints. CONCLUSIONS We provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono-arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions.
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Affiliation(s)
- Elizabeth S Fernandes
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK. .,Programa de Pós-Graduação, Universidade Ceuma, São Luís, MA, 65075-120, Brazil.
| | - Fiona A Russell
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Khadija M Alawi
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Claire Sand
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Lihuan Liang
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Robin Salamon
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Jennifer V Bodkin
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Aisah A Aubdool
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Matthew Arno
- Genomics Centre, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Clive Gentry
- Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, SE1 1UL, UK.
| | - Sarah-Jane Smillie
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Stuart Bevan
- Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, SE1 1UL, UK.
| | - Julie E Keeble
- Institute of Pharmaceutical Science, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
| | - Marzia Malcangio
- Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, SE1 1UL, UK.
| | - Susan D Brain
- Centre for Cardiovascular Excellence, Waterloo Campus, King's College London, Franklin-Wilkins Building, 150 Stamford St, London, SE1 9NH, UK.
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Khenioui H, Houvenagel E, Catanzariti JF, Guyot MA, Agnani O, Donze C. Usefulness of intra-articular botulinum toxin injections. A systematic review. Joint Bone Spine 2015; 83:149-54. [PMID: 26645160 DOI: 10.1016/j.jbspin.2015.10.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2015] [Indexed: 10/22/2022]
Abstract
UNLABELLED Botulinum toxin is a proven and widely used treatment for numerous conditions characterized by excessive muscular contractions. Recent studies have assessed the analgesic effect of botulinum toxin in joint pain and started to unravel its mechanisms. LITERATURE-SEARCH-METHODOLOGY We searched the international literature via the Medline database using the term "intraarticular botulinum toxin injection" combined with any of the following terms: "knee", "ankle", "shoulder", "osteoarthritis", "adhesive capsulitis of the shoulder". RESULTS Of 16 selected articles about intraarticular botulinum toxin injections, 7 were randomized controlled trials done in patients with osteoarthritis, adhesive capsulitis of the shoulder, or chronic pain after joint replacement surgery. Proof of anti-nociceptive effects was obtained in some of these indications and the safety and tolerance profile was satisfactory. The studies are heterogeneous. The comparator was usually a glucocorticoid or a placebo; a single study used hyaluronic acid. Pain intensity was the primary outcome measure. DISCUSSION-CONCLUSION The number of randomized trials and sample sizes are too small to provide a satisfactory level of scientific evidence or statistical power. Unanswered issues include the effective dosage and the optimal dilution and injection modalities of botulinum toxin.
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Affiliation(s)
- Hichem Khenioui
- Service de médecine physique et de réadaptation, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Université catholique de Lille, 60, boulevard Vauban, 59800 Lille, France.
| | - Eric Houvenagel
- Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Université catholique de Lille, 60, boulevard Vauban, 59800 Lille, France; Service de rhumatologie, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France
| | - Jean François Catanzariti
- Service de médecine physique et de réadaptation, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Service de rhumatologie, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Service de médecine physique et réadaptation, centre de SSR pédiatrique Marc-Sautelet, 10, rue du Petit-Boulevard, 59650 Villeneuve-d'Ascq, France
| | - Marc Alexandre Guyot
- Service de médecine physique et de réadaptation, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Service de rhumatologie, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France
| | - Olivier Agnani
- Service de médecine physique et de réadaptation, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Service de rhumatologie, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France
| | - Cécile Donze
- Service de médecine physique et de réadaptation, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France; Université Nord de France, 1, rue Lefèvre, 59000 Lille, France; Service de rhumatologie, centre hospitalier Saint-Philibert, groupe hospitalier de l'institut catholique de Lille, 115, rue du Grand-But, BP 249, 59462 Lomme cedex, France
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Takano S, Uchida K, Miyagi M, Inoue G, Aikawa J, Fujimaki H, Minatani A, Sato M, Iwabuchi K, Takaso M. Synovial macrophage-derived IL-1β regulates the calcitonin receptor in osteoarthritic mice. Clin Exp Immunol 2015; 183:143-9. [PMID: 26400621 DOI: 10.1111/cei.12712] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2015] [Indexed: 12/26/2022] Open
Abstract
Recent studies have reported that calcitonin gene-related peptide (CGRP) contributes to joint pain. However, regulation of the CGRP/CGRP receptor signalling in osteoarthritis (OA) is not fully understood. To investigate the regulation of CGRP/CGRP receptor signalling by macrophages in the synovial tissue (ST) of OA joints, we characterized the gene expression profiles of CGRP and CGRP receptors in the ST of OA mice (STR/Ort). In addition, we examined whether macrophage depletion by the systemic injection of clodronate-laden liposomes affected the expression of CGRP and CGRP receptors in ST. CD11c(+) macrophages in the ST of STR/Ort and C57BL/6J mice were analysed by flow cytometry. Real-time polymerase chain reaction (PCR) was used to evaluate the expression of interleukin (IL)-1β, CGRP, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in F4/80(+) and F4/80(-) cells. The effects of IL-1β on the expression of CGRP and CLR by cultured synovial cells were also examined. The percentage of CD11c(+) macrophages in the ST of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80(+) cell fraction expressed IL-1β highly, whereas the F4/80(-) cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL-1β and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL-1β treatment of cultured synovial cells up-regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL-1β and regulators of CLR in OA mice. Therefore, macrophages and IL-1β may be suitable therapeutic targets for treating OA pain.
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Affiliation(s)
- S Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - K Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - M Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - G Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - J Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - H Fujimaki
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - A Minatani
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - M Sato
- Department of Immunology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - K Iwabuchi
- Department of Immunology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - M Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
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Lisowska B, Lisowski A, Siewruk K. Substance P and Chronic Pain in Patients with Chronic Inflammation of Connective Tissue. PLoS One 2015; 10:e0139206. [PMID: 26444559 PMCID: PMC4622041 DOI: 10.1371/journal.pone.0139206] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/10/2015] [Indexed: 11/30/2022] Open
Abstract
Objective Evidence suggests that substance P (SP) is involved in chronic joint inflammation, such as the pathogenesis of rheumatoid arthritis and osteoarthritis. The goal of the research was to evaluate the correlation between chronic pain and changes in the SP level in patients with chronic inflammation of the connective tissue. Methods Patients with osteoarthritis and rheumatoid arthritis were enrolled in this study. The relationship between chronic pain intensity and the serum SP concentration was evaluated in these groups of patients with osteoarthritis and rheumatoid arthritis. Results The results showed a positive correlation between the serum SP concentrations and chronic pain intensity. Conclusions 1. The SP serum concentration was significantly different between the groups of patients with OA and RA. 2. There was a positive correlation between the serum SP concentration and chronic pain intensity in OA and RA patients.
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Affiliation(s)
- Barbara Lisowska
- Department of Anaesthesiology, Medical Centre for Postgraduate Education, Adam Gruca Clinical Hospital, Postgraduate Medical Education Centre, Otwock, Poland
| | - Aleksander Lisowski
- Faculty of Production Engineering, Warsaw University of Life Sciences, Warsaw, Poland
| | - Katarzyna Siewruk
- Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
- * E-mail:
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