Mohawk is a transcription factor that promotes meniscus cell phenotype and tissue repair and reduces osteoarthritis severity

Mohawk is enriched in meniscal tissue and promotes meniscus cell phenotype, enhances repair, and protects against cartilage destruction in mice. Managing meniscus maladies Knee osteoarthritis can develop from meniscus tears that do not heal. Lee et al. investigated transcription factors that regulate meniscus cell biology. They found that Mohawk (MKX) was enriched in meniscus, induced meniscus-like differentiation in mesenchymal stem cells (MSCs), and suppressed genes related to osteoarthritis and meniscus degeneration and calcification. Treating bovine decellularized meniscus scaffolds with MKX-transduced MSCs improved meniscus healing, and injecting adenoviral MKX into mouse knee joints protected against cartilage damage in a model of osteoarthritis. This suggests that MKX may be a therapeutic target for meniscus injury and osteoarthritis. Meniscus tears are common knee injuries and a major osteoarthritis (OA) risk factor. Knowledge gaps that limit the development of therapies for meniscus injury and degeneration concern transcription factors that control the meniscus cell phenotype. Analysis of RNA sequencing data from 37 human tissues in the Genotype-Tissue Expression database and RNA sequencing data from meniscus and articular cartilage showed that transcription factor Mohawk (MKX) is highly enriched in meniscus. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). In mesenchymal stem cells (MSCs), the combination of adenoviral MKX (Ad-MKX) and transforming growth factor–β3 (TGF-β3) induced a meniscus cell phenotype. When Ad-MKX–transduced MSCs were seeded on TGF-β3–conjugated decellularized meniscus scaffold (DMS) and inserted into experimental tears in meniscus explants, they increased glycosaminoglycan content, extracellular matrix interconnectivity, cell infiltration into the DMS, and improved biomechanical properties. Ad-MKX injection into mouse knee joints with experimental OA induced by surgical destabilization of the meniscus suppressed meniscus and cartilage damage, reducing OA severity. Ad-MKX injection into human OA meniscus tissue explants corrected pathogenic gene expression. These results identify MKX as a previously unidentified key transcription factor that regulates the meniscus cell phenotype. The combination of Ad-MKX with TGF-β3 is effective for differentiation of MSCs to a meniscus cell phenotype and useful for meniscus repair. MKX is a promising therapeutic target for meniscus tissue engineering, repair, and prevention of OA.

[1]  A. Su,et al.  Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis. , 2018, Osteoarthritis and cartilage.

[2]  D. D’Lima,et al.  Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears. , 2018, Acta biomaterialia.

[3]  Benjamin B. Rothrauff,et al.  Region-Specific Effect of the Decellularized Meniscus Extracellular Matrix on Mesenchymal Stem Cell–Based Meniscus Tissue Engineering , 2017, The American journal of sports medicine.

[4]  D. D’Lima,et al.  Relevance of meniscal cell regional phenotype to tissue engineering , 2017, Connective tissue research.

[5]  T. Sasho,et al.  Increased DNA Methylation and Reduced Expression of Transcription Factors in Human Osteoarthritis Cartilage , 2016, Arthritis & rheumatology.

[6]  Benjamin J. Ainscough,et al.  High-performance web services for querying gene and variant annotation , 2016, Genome Biology.

[7]  D. D’Lima,et al.  Histopathological analyses of murine menisci: implications for joint aging and osteoarthritis. , 2016, Osteoarthritis and cartilage.

[8]  D. D’Lima,et al.  Repair of Avascular Meniscus Tears with Electrospun Collagen Scaffolds Seeded with Human Cells , 2016, Tissue engineering. Part A.

[9]  C. A. Toro,et al.  Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression , 2015, Nature Communications.

[10]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[11]  F. Eckstein,et al.  What Comes First? Multitissue Involvement Leading to Radiographic Osteoarthritis: Magnetic Resonance Imaging–Based Trajectory Analysis Over Four Years in the Osteoarthritis Initiative , 2015, Arthritis & rheumatology.

[12]  N. Südkamp,et al.  Associated tears of the lateral meniscus in anterior cruciate ligament injuries: risk factors for different tear patterns , 2015, Journal of Orthopaedic Surgery and Research.

[13]  I. Sekiya,et al.  Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo , 2015, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[14]  Jeremy J. Mao,et al.  Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep , 2014, Science Translational Medicine.

[15]  V. Rosen,et al.  Human Migratory Meniscus Progenitor Cells Are Controlled via the TGF-β Pathway , 2014, Stem cell reports.

[16]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[17]  C. Evans.  Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues , 2014, International Orthopaedics.

[18]  G. Smyth,et al.  voom: precision weights unlock linear model analysis tools for RNA-seq read counts , 2014, Genome Biology.

[19]  V. Rosen,et al.  Gene signature of the embryonic meniscus , 2014, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[20]  D. Patra,et al.  Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. , 2013, Arthritis and rheumatism.

[21]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[22]  D. D’Lima,et al.  Zone-specific gene expression patterns in articular cartilage. , 2013, Arthritis and rheumatism.

[23]  R. Mauck,et al.  Growth factor supplementation improves native and engineered meniscus repair in vitro. , 2012, Acta biomaterialia.

[24]  James J. Yoo,et al.  The effect of controlled release of PDGF-BB from heparin-conjugated electrospun PCL/gelatin scaffolds on cellular bioactivity and infiltration. , 2012, Biomaterials.

[25]  Yubo Sun,et al.  Meniscal calcification, pathogenesis and implications , 2012, Current opinion in rheumatology.

[26]  J. Hecht,et al.  Comparative analysis with collagen type II distinguishes cartilage oligomeric matrix protein as a primary TGFβ-responsive gene. , 2011, Osteoarthritis and cartilage.

[27]  Kyriacos A Athanasiou,et al.  The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. , 2011, Biomaterials.

[28]  D. D’Lima,et al.  Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis. , 2011, Osteoarthritis and cartilage.

[29]  M. Guerquin,et al.  EGR1 and EGR2 Involvement in Vertebrate Tendon Differentiation* , 2010, The Journal of Biological Chemistry.

[30]  C. Little,et al.  The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. , 2010, Osteoarthritis and cartilage.

[31]  J. Mao,et al.  CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. , 2010, The Journal of clinical investigation.

[32]  Thomas L. Smith,et al.  An acellular, allograft-derived meniscus scaffold in an ovine model. , 2010, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[33]  L. Prantl,et al.  Hypertrophy in Mesenchymal Stem Cell Chondrogenesis: Effect of TGF-β Isoforms and Chondrogenic Conditioning , 2010, Cells Tissues Organs.

[34]  F. Guilak,et al.  Chondrogenesis of adult stem cells from adipose tissue and bone marrow: induction by growth factors and cartilage-derived matrix. , 2010, Tissue engineering. Part A.

[35]  Davis J. McCarthy,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[36]  L. Engebretsen,et al.  Winner of the 2008 Systematic Review Competition: Knee Osteoarthritis after Anterior Cruciate Ligament Injury , 2009, The American journal of sports medicine.

[37]  Minghua Wu,et al.  Smad-independent transforming growth factor-beta regulation of early growth response-1 and sustained expression in fibrosis: implications for scleroderma. , 2008, The American journal of pathology.

[38]  Thomas L. Smith,et al.  A naturally derived, cytocompatible, and architecturally optimized scaffold for tendon and ligament regeneration. , 2007, Biomaterials.

[39]  S. Glasson,et al.  The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. , 2007, Osteoarthritis and cartilage.

[40]  C. Pilapil,et al.  Genetically enhanced engineering of meniscus tissue using ex vivo delivery of transforming growth factor-beta 1 complementary deoxyribonucleic acid. , 2007, Tissue engineering.

[41]  Thomas Aigner,et al.  Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. , 2006, Arthritis and rheumatism.

[42]  Stacy M. Imler,et al.  Combined effects of growth factors and static mechanical compression on meniscus explant biosynthesis. , 2004, Osteoarthritis and cartilage.

[43]  W. Russell,et al.  Update on adenovirus and its vectors. , 2000, The Journal of general virology.

[44]  P. Robbins,et al.  Genetically augmented tissue engineering of the musculoskeletal system. , 1999, Clinical orthopaedics and related research.

[45]  M. Perricaudet,et al.  Adenovirus vectors for gene delivery. , 1999, Current opinion in biotechnology.

[46]  K. Dehaven,et al.  Meniscus Repair , 1999, The American journal of sports medicine.

[47]  D. Bickerstaff,et al.  The natural history of meniscal tears in anterior cruciate ligament insufficiency , 1993, The American journal of sports medicine.

[48]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[49]  Meniscal Repair , 2006 .

[50]  A. Scala,et al.  Different patterns of meniscal tears in acute anterior cruciate ligament (ACL) ruptures and in chronic ACL-deficient knees , 2005, Knee Surgery, Sports Traumatology, Arthroscopy.

[51]  I Petersen,et al.  Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology. , 2002, Pathology, research and practice.

[52]  K. Kinzler,et al.  A simplified system for generating recombinant adenoviruses. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[53]  G. Müller,et al.  COMP (cartilage oligomeric matrix protein) is synthesized in ligament, tendon, meniscus, and articular cartilage. , 1998, Connective tissue research.

[54]  Thomas Lengauer,et al.  Bioinformatics Original Paper Improved Scoring of Functional Groups from Gene Expression Data by Decorrelating Go Graph Structure , 2022 .

[55]  D. Gagnon,et al.  A R T I C L E , 2022 .