Gonçalves, Raquel M

Riegger, Jana

Risbud, Makarand V.

Teixeira, Graciosa Q

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Department of Orthopaedic Surgery Faculty Papers Department of Orthopaedic Surgery 7-26-2023 Editorial: Intervertebral disc degeneration and osteoarthritis: mechanisms of disease and functional repair. Graciosa Q Teixeira Jana Riegger Raquel M Gonçalves Makarand V. Risbud Follow this and additional works at: https://jdc.jefferson.edu/orthofp  Part of the Molecular, Cellular, and Tissue Engineering Commons, Orthopedics Commons, and the Surgery Commons Let us know how access to this document benefits you This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Orthopaedic Surgery Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. Editorial: Intervertebral discdegeneration and osteoarthritis:mechanisms of disease andfunctional repairGraciosa Q. Teixeira1*, Jana Riegger2, Raquel M. Gonçalves3,4,5and Makarand V. Risbud6,71Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre, Ulm University, Ulm,Germany, 2Department of Orthopedics, Division for Biochemistry of Joint and Connective TissueDiseases, UlmUniversity, Ulm, Germany, 3Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal, 4Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal,5Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal, 6Department ofOrthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA,United States, 7Graduate Program in Cell Biology and Regenerative Medicine, College of Life Sciences,Thomas Jefferson University, Philadelphia, PA, United StatesKEYWORDSintervertebral disc (IVD), cartilage, degeneration, biomechanics, inflammation,regeneration, tissue engineeringEditorial on the Research TopicIntervertebral disc degeneration and osteoarthritis: mechanisms of diseaseand functional repairIntervertebral disc (IVD) degeneration and osteoarthritis (OA) are the leadingmusculoskeletal causes of disability worldwide, with a considerable loss of productivity andhigh healthcare costs. Both diseases are associated with severe pain, affecting about 90% of theover 50 years old (IVD) and more than 50% of the over 65 years old (OA) population. Currenttreatments, varying from physiotherapy to invasive surgery, carry high costs. These approachesmay alleviate pain and improve mobility in the short run, but do not target the underlying causesof tissue degeneration. IVD, articular cartilage, and meniscus are tissues that share somesimilarities in cellular metabolism and matrix homeostasis in health and disease. Particularlyduring pathogenesis, there is a strong interplay between tissue degradation, inflammation, andoverall immune response, which has not been fully understood so far.It is essential to identify pathophysiologic key molecules and pathways that could be targetedby means of molecular medicine, pharmacologic, and tissue engineering strategies to promotecartilaginous tissue repair/regeneration,mainly bymodulating the immune response. It should beconsidered that similar approaches might be effective for IVD, articular cartilage, and meniscus.Especially in the case of young, active patients, regenerative strategies including administration ofbioactive molecules and cell transplantation alone or in combination with scaffolds, have beeninvestigated for IVD regeneration and articular joint repair over the past two decades, showingpromising results in vivo and in clinical trials. Nevertheless, for the development of innovative,off-the-shelf, and long-term effective regenerative strategies, it is important to understand themolecular mechanisms underlying the disease and, in particular, the interplay between matrixbreakdown and the local and systemic immune response. For instance, the affected IVD or jointpresents a hostile inflammatory environment challenging for the long-term effect of homingOPEN ACCESSEDITED AND REVIEWED BYAndrea Vernengo,AO Research Institute, Switzerland*CORRESPONDENCEGraciosa Q. Teixeira,graciosa.teixeira@uni-ulm.deRECEIVED 04 July 2023ACCEPTED 21 July 2023PUBLISHED 26 July 2023CITATIONTeixeira GQ, Riegger J, Gonçalves RMand Risbud MV (2023), Editorial:Intervertebral disc degeneration andosteoarthritis: mechanisms of diseaseand functional repair.Front. Bioeng. Biotechnol. 11:1252703.doi: 10.3389/fbioe.2023.1252703COPYRIGHT© 2023 Teixeira, Riegger, Gonçalves andRisbud. This is an open-access articledistributed under the terms of theCreative Commons Attribution License(CC BY). The use, distribution orreproduction in other forums ispermitted, provided the original author(s)and the copyright owner(s) are creditedand that the original publication in thisjournal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.Frontiers in Bioengineering and Biotechnology frontiersin.org01TYPE EditorialPUBLISHED 26 July 2023DOI 10.3389/fbioe.2023.1252703tissue cells or engraftment of transplanted cells. Therefore, there is anurgent need for alternative approaches to modulate inflammation andmatrix degeneration, in order to stimulate tissue repair/regeneration.This Research Topic includes a Research Topic of six articles thataddress a broad range of relevant questions including a workinvestigating the delamination of annulus fibrosus using bovinemodel (Briar et al.), a study on the role of aggrecan in themaintenance of the physiologic stiffness of the IVD (Empere et al.),and the development of a human 3D nucleus pulposus (NP)microtissue (µT) model to evaluate the potential of pre-conditionednasal chondrocytes for the repair of degenerated IVDs (Kasamkattilet al.). In addition, Habib et al. investigated the effect of intradiscaldelivery of a matrix-modifying enzyme to the cartilage endplate. Thesepublications contribute to a better understanding of the physiology andbiomechanical characteristics of the different IVD compartments andoutline new potential therapeutic strategies to improve thebiomechanical behavior of the degenerated IVD. In addition, thisResearch Topic comprises two publications focused on cartilage andOA. The work from Riegger et al. investigated the effect of simvastatinand fluvastatin to attenuate cell death and catabolism in humancartilage after ex vivo trauma. Lastly, an opinion article on the usageof low-level laser therapy in patients with knee joint OA summarizedthe relevant literature on the effectiveness, as well as implications of thistherapeutic approach (Khumaidi et al.).Briar et al. investigated the influence of delamination rate on theadhesive properties of the layer-adjoining interlamellar matrix ofannulus fibrosus from bovine tail IVDs at different rates ofseparation. The annulus fibrosus stretches under tension and,therefore, this is a relevant work to better understand themechanical behavior of this under-investigated IVDcompartment (in comparison to the NP), as the spineexperiences various loading velocities during activities of dailyliving. Overall, no differences in lamellar adhesion strength orstiffness were observed across all loading rates. However, lamellaradhesion strength variability was observed to increase with anincreasing rate of delamination, possibly highlighting aviscoelastic response to this structure. According to the authors,such mechanical behavior may permit the development ofmicrotrauma at lower overall levels of force, and thereby presentan injury scenario in which the disc becomes more susceptible todelamination (Briar et al.).Empere et al. provided a deeper understanding of aggrecan(ACAN) within the IVD compartments by taking advantage ofgenetically engineered mouse models. By generating an ACANinsertion mutant mice (AcaniE5/iE5) the authors reportedcompressed vertebral bodies with accelerated mineralization inACAN mutants compared to wild type controls. Furthermore,collapsed extracellular matrix with negligible sulfatedglycosaminoglycan content accompanied by a high cellulardensity was observed in AcaniE5/iE5 mice, without impairingcollagen type II deposition. Severe alterations in cartilageendplates (CEP), NP structure, and growth plate were observed,from the macroscopic to the nanoscale level. Taken together, theteam demonstrated the importance of aggrecan to the maintenanceof the proper stiffness of IVD and vertebral tissues.In addition, Kasamkattil et al. developed an advanced 3D NPµTmodel that could be used to test the performance of nasalchondrocytes (NC) suspension or spheroids (NCS) after pre-conditioning with drugs known to exert anti-inflammatory oranabolic activities. Degenerative NPµT contained lowerconcentration of glycosaminoglycans and collagens and releasedhigher levels of interleukin-8 (IL-8) compared to the healthy NPµT.Interleukin-1 receptor antagonist (IL-1Ra) pre-conditioninginhibited the expression of inflammatory/catabolic mediators andpromoted glycosaminoglycan accumulation in NC/NCS in thedegenerative IVD microenvironment. The degenerative NPµTmodel is suitable to study the responses of therapeutic cells tomicroenvironment mimicking early-stage degenerative discdisease. NC in spheroidal organization exhibited superiorregenerative performance compared to NC cell suspension. IL-1Ra pre-conditioning of NCS could further improve the NCability to counteract inflammation/catabolism and support newmatrix production within the harsh degenerativemicroenvironment in disc disease.CEP nutrient transport, a key factor in the etiology ofintervertebral disc degeneration, was also addressed in thepresent Research Topic. Habib et al. tested whether intradiscaldelivery of a matrix-modifying enzyme to the CEP improvessolute transport into whole human and bovine discs. In fact, theenzymatic treatment of the CEP dramatically enhanced small solutetransport in both tissue models, without affecting discbiomechanical behavior, demonstrating a potential benefit formatrix modification of the CEP to promote the transport ofsmall solutes into whole intact IVDs.In their study on the therapeutic effects of Fluvastatin andSimvastatin after ex vivo cartilage trauma, Riegger et al. observedcell and chondroprotective effects for both statins. However, thepotent anti-catabolic and antioxidative properties of the drugs alsocompromised chondrogenic re-differentiation of humanchondrocytes, when permanently applied, as demonstrated in a3D pellet culture model. Although chondrogenic re-differentiation was recovered and even increased after short-termtreatment using low concentrations of Simvastatin, thisconcentration was less effective in cell protection after cartilagetrauma. The authors concluded that statin therapy does not directlycontribute to cartilage regeneration, but might be a suitableapproach to prevent injury-induced cartilage degeneration andthus reduce the risk of posttraumatic OA.The opinion article from Khumaidi et al. argues that low levellaser therapy (LLLT), which is the electronic level absorption of laserlight without the production of heat in the visible to near infraredspectral spectrum (390–1100 nm), can be used as a non-invasivetreatment modality for knee OA patient. Based on literature findings,the authors defend that in combination with physical exercises, LLLTmay result in reduced inflammation, improvement in WesternOntario and McMaster Universities Osteoarthritis Index(WOMAC) scores, pain, range of motion, and functional status inknee OA patients via photobiomodulation. However, Khumaidi et al.call for rigorous and standardized research to overcome currentvariability in laser application research methodology and the lackof laser type data, dose range research, and wavelength selection.The articles in this Research Topic elucidate the behavior of IVDstructures and mechanisms involved in IVDD and post-traumaticOA, and/or propose novel therapeutic approaches for thecartilaginous structures. We hope this contributes to a betterunderstanding of the degeneration-associated processes and thatFrontiers in Bioengineering and Biotechnology frontiersin.org02Teixeira et al. 10.3389/fbioe.2023.1252703the proposed therapeutic approaches may have the potential toimprove patient care in the future.Author contributionsGT, RG, and MR have overseen the entire Research Topic. GT,JR, and RG wrote the original draft of this editorial with editinginput and advice fromMR. All authors contributed to the article andapproved the submitted version.AcknowledgmentsWe would like to acknowledge all the authors whosepublications were included in this Research Topic.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Frontiers in Bioengineering and Biotechnology frontiersin.org03Teixeira et al. 10.3389/fbioe.2023.1252703

Editorial: Intervertebral disc degeneration and osteoarthritis: mechanisms of disease and functional repair.

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Editorial: Intervertebral disc degeneration and osteoarthritis: mechanisms of disease and functional repair.

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