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Genetic Murine Models of Spinal Development and Degeneration Provide Valuable Insights Into Intervertebral Disc Pathobiology

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Genetic Murine Models of Spinal Development and Degeneration Provide Valuable Insights Into Intervertebral Disc Pathobiology EuropeanJ Melrose etCells al. and Materials Vol. 41 2021 (pages 52-72) DOI: 10.22203/eCM.v041a05 Murine ISSN spine 1473-2262 models GENETIC MURINE MODELS OF SPINAL DEVELOPMENT AND DEGENERATION PROVIDE VALUABLE INSIGHTS INTO INTERVERTEBRAL DISC PATHOBIOLOGY J. Melrose1,2,3,§,*, S. Tessier4,5,§ and M.V. Risbud5,6,* 1 Research Associate, Kolling Institute of Medical Research and the Institute of Bone and Joint Research, North Sydney Area Health Authority, University of Sydney at the Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia 2 Department of Surgery, Northern Clinical School, University of Sydney, Australia 3 Professor Graduate School of Biomedical Engineering, The University of New South Wales, Australia 4 Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA 5 Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 6 Graduate Program in Cell Biology and Regenerative Medicine, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, USA § These authors contributed equally to this work Abstract Disc degeneration and associated back and neck pain elicits a substantial burden on healthcare systems and the individuals affected, necessitating the development of novel therapeutic strategies. This goal can only be achieved by a better understanding of intervertebral disc development, homeostasis and pathogenesis. A number of genetic and in-bred murine models are reviewed to underscore the importance of the mouse as an animal model of choice for the assessment of intervertebral disc pathobiology. Appraisals of the differences between mouse and human musculoskeletal systems and proteoglycan structures are also included. A number of important target pathways and molecules have been identified, many of which are worthy of further examination, requiring that the activity of these be confirmed in large animal models and assessed in the context of therapeutic intervention. Keywords: Murine model, intervertebral disc, nucleus pulposus, annulus fibrosus, spine. *Address for correspondence: Makarand V. Risbud, PhD, Department of Orthopaedic Surgery, Thomas Jefferson University, 1025 Walnut Street, Suite 501 College Bldg., Philadelphia, PA 19107, USA. Fax number: +1 215 9559159 Email: [email protected] Copyright policy: This article is distributed in accordance with Creative Commons Attribution Licence (http://creativecommons.org/licenses/by-sa/4.0/). List of Abbreviations BACH-1 BTB and CNC homology-1 BGN biglycan ADAMTS a disintegrin and BMP bone morphogenic protein metalloproteinase with BNIP3 BLC2 interacting protein 3 thrombospondin motifs CA3 carbonic anhydrase 3 AF annulus fibrosus Can aggrecan Akr1b1 aldo-keto reductase family 1 Ccl2 monocyte chemoattractant member B protein-1, aka MCP-1 ALPL alkaline phosphatase CD44 cluster of differentiation 44 ANK ankyrin CDK2 cyclin-dependent kinase 2 AP-1 activator protein 1 CEP cartilaginous endplates Aqp2 aquaporin-2 Chm1 chondromodulin I ARP2/3 actin-related proteins 2/3 COL1A1 collagen type I alpha chain ATM ataxia-telangiectasia mutated COL2A1 collagen type II alpha chain kinase COX-2 cyclooxygenase-2 B3gat3 beta-1,3-glucuronyltransferase 3 CS chondroitin sulphate www.ecmjournal.org 52 J Melrose et al. Murine spine models CTGF connective tissue growth factor NP nucleus pulposus E2F elongation factor 2 OREBP osmotic response element binding ENPP1 ectonucleotide pyrophosphatase/ protein phosphodiesterase 1 p16 cyclin-dependent kinase inhibitor ENT1 equilibrative nucleoside 2A transporter 1 PAX1/9 paired box 1/9 ERCC1 excision repair 1 endonuclease PHLPP1 PH domain leucine-rich repeat non-catalytic subunit protein phosphatase ERK extracellular signal-regulated PRG4 lubricin kinase Pt Pintail FasL Fas ligand PTCH1 Patched 1 FGF fibroblast growth factor QTL quantitative trait locus FGFRs fibroblast growth factor receptors RAS rat sarcoma FLNB filamin B RB1 retinoblastoma transcriptional FMOD fibromodulin corepressor 1 FOXA1/2 forkhead box A1/A2 RHAMM receptor for HA-mediated motility FOXO1/3/4 forkhead box O1/O3/O4 SCX scleraxis GAG glycosaminoglycan Sd Danforths short tail Gal D-galactose SHH Sonic Hedgehog GalNAc N-acetylgalactosamine Skt Sickle tail GDF5 growth differentiation factor 5 Slc6A6 sodium- and chloride-dependent GlcA glucuronic acid taurine transporter GlcNAc β1-3 D-N-acetylglucosamine SLRP small leucine-rich proteoglycan GlcUA glucuronic acid SMAD3 mothers against decapentaplegic HA hyaluronic acid homologue 3 HAS2 hyaluronan synthase 2 Smo smoothened HIF-1/2α hypoxia-inducible factor SOX5/6/9 Sry-related HMG box 5/6/9 1alpha/2alpha SPARC secreted protein acidic and rich in HO-1 haem oxygenase-1 cysteine HOX homeobox T brachyury HS heparan sulphate Tc truncate Hspg2 perlecan Tgfb2 TGF-β type II receptor IGD interglobular domain TGF-β transforming growth factor beta IGF-1 insulin-like growth factor 1 TNF-α tumour necrosis factor alpha IGFR insulin-like growth factor receptor TNMD tenomodulin IL-1rn interleukin 1 receptor antagonist TonEBP tonicity enhancer binding protein IL-1α/β interleukin 1 alpha/beta TSC tuberous sclerosis complex IL-6 interleukin-6 VEGF vascular endothelial growth factor IVD intervertebral disc WNT wingless/integrated JNK1/2 Jun N-terminal kinase 1/2 KS keratan sulphate LAMSHF Lamb-Shaffer syndrome Introduction LDL low density lipoprotein LDLR low density lipoprotein receptor Insight into disc pathobiology through the LP link protein murine model LRP6 low-density lipoprotein receptor- The murine model is an invaluable experimental related protein 6 tool for the investigation of several degenerative MAPK mitogen-activated protein kinase human conditions. Studies of a number of genetically MCP-1 monocyte chemoattractant modified mice have contributed immensely to protein-1 our understanding of spinal development and MCT4 monocarboxylate transporter 4 homeostasis (Table 1-4). Indeed, manipulations of the MKX Mohawk mouse genome through mis-expression, knocking- MMP matrix metalloproteinase out, knocking-in, or the introduction of mutations MT1-MMP membrane type 1-matrix into genes, as well as inbred mouse models, metalloproteinase, aka MMP14 have transformed our understanding of spinal mTOR mechanistic target of rapamycin development and the complex functional properties NF-1 neurofibromatosis type 1 of the IVD. In many cases, such mutants are also NFAT5 nuclear factor of activated T-cells 5 genetic models of relevant human degenerative NF-κB nuclear factor kappa-light-chain- disorders characterised by, for example, reduced bone enhancer of activated B cells mass (osteopenia, osteoporosis) or abnormalities in NOTO homeobox protein notochord endochondral bone formation affecting development 53 www.ecmjournal.org J Melrose et al. Murine spine models and growth of the skeleton (chondrodysplasias). The polyaxial, diarthrodial joint that allows for wide value of the murine model is further underscored ranges of 3-dimensional movement (Shapiro et al., by the high conservation of skeletal development 2012). between mice and humans, despite differences The murine IVD shares the structural characteristics in skeletal size and time required for reaching described above with that of humans. An important skeletal maturity. From a regenerative perspective, difference to highlight, nonetheless, is that notochord- understanding the regulatory molecules that are like NP cells persist longer in the murine model operative during such developmental processes than in humans. The murine and human IVD are provides information applicable to therapeutic tissue embryonically derived from the aggregation of the repair strategies (Tessier and Risbud, 2020). Moreover, notochord and perinotochordal mesenchyme during the development of quantitative histopathological vertebral column development. Notochordal cells scoring schemes for murine IVDs have further produce a matrix rich in proteoglycan, important for increased the utility of the murine model for generating central swelling pressure in the developing pathobiological evaluations. It is within this context IVD and essential for normal NP formation (Adams et that we have summarised numerous studies, whose al., 1977). In humans, within 4 to 10 years of age after insightful conclusions relied heavily upon the use of birth, the notochordal cells of the disc disappear or the mouse as an experimental model. undergo significant morphological changes, whereas they persist throughout adulthood in the healthy Intervertebral disc structure and comparative murine system (Trout et al., 1982). Human NP cells anatomy acquire a round, chondrocytic appearance as they The spinal column was evolutionarily preceded by age, becoming increasingly dispersed throughout the the notochord, a rod-like structure that provided matrix. By contrast, the adult vacuolated NP cells of protection to the underlying neural tube and the healthy mouse disc assemble into a central band. mechanical support to the chordate organism. In For reference to the histomorphology of human disc higher vertebrates, which possess the advantage tissue, please consult the studies cited here (Boos et of distinct spinal joints (syndesmosis/symphysis) al., 2002; Rutges et al., 2013). Notochordal NP cells consisting of mineralised vertebral bodies joined are large and vacuolated, often forming groups and by IVDs, the notochord exits as merely a transient clusters and described as a physaliforous cell type embryonic structure. While transient, it
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