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  1. Article ; Online: Understanding the Transcriptomic Landscape to Drive New Innovations in Musculoskeletal Regenerative Medicine.

    Thomas, Stacey M / Ackert-Bicknell, Cheryl L / Zuscik, Michael J / Payne, Karin A

    Current osteoporosis reports

    2022  Volume 20, Issue 2, Page(s) 141–152

    Abstract: Purpose of review: RNA-sequencing (RNA-seq) is a novel and highly sought-after tool in the field of musculoskeletal regenerative medicine. The technology is being used to better understand pathological processes, as well as elucidate mechanisms ... ...

    Abstract Purpose of review: RNA-sequencing (RNA-seq) is a novel and highly sought-after tool in the field of musculoskeletal regenerative medicine. The technology is being used to better understand pathological processes, as well as elucidate mechanisms governing development and regeneration. It has allowed in-depth characterization of stem cell populations and discovery of molecular mechanisms that regulate stem cell development, maintenance, and differentiation in a way that was not possible with previous technology. This review introduces RNA-seq technology and how it has paved the way for advances in musculoskeletal regenerative medicine.
    Recent findings: Recent studies in regenerative medicine have utilized RNA-seq to decipher mechanisms of pathophysiology and identify novel targets for regenerative medicine. The technology has also advanced stem cell biology through in-depth characterization of stem cells, identifying differentiation trajectories and optimizing cell culture conditions. It has also provided new knowledge that has led to improved growth factor use and scaffold design for musculoskeletal regenerative medicine. This article reviews recent studies utilizing RNA-seq in the field of musculoskeletal regenerative medicine. It demonstrates how transcriptomic analysis can be used to provide insights that can aid in formulating a regenerative strategy.
    MeSH term(s) Cell Culture Techniques ; Humans ; Musculoskeletal System ; Regenerative Medicine ; Stem Cells ; Tissue Engineering ; Transcriptome
    Language English
    Publishing date 2022-02-14
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2186581-4
    ISSN 1544-2241 ; 1544-1873
    ISSN (online) 1544-2241
    ISSN 1544-1873
    DOI 10.1007/s11914-022-00726-x
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  2. Article: GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density.

    Conery, Mitchell / Pippin, James A / Wagley, Yadav / Trang, Khanh / Pahl, Matthew C / Villani, David A / Favazzo, Lacey J / Ackert-Bicknell, Cheryl L / Zuscik, Michael J / Katsevich, Eugene / Wells, Andrew D / Zemel, Babette S / Voight, Benjamin F / Hankenson, Kurt D / Chesi, Alessandra / Grant, Struan F A

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. ... ...

    Abstract Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblast 1.19 cells (hFOBs). The BMD relevance of hFOBs was supported by heritability enrichment from cross-cell type stratified LD-score regression involving 98 cell types grouped into 15 tissues. 24 genes showed perturbation in the screen, with four (
    Language English
    Publishing date 2024-03-20
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.19.585778
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  3. Article ; Online: Surgical Induction of Posttraumatic Osteoarthritis in the Mouse.

    Maynard, Robert D / Villani, David A / Schroeder, William G / Adams, Douglas J / Zuscik, Michael J

    Methods in molecular biology (Clifton, N.J.)

    2020  Volume 2230, Page(s) 91–103

    Abstract: Given the prevalence and the scope of the personal and societal burden of osteoarthritis (OA), investigators continue to be deeply interested in understanding the pathogenic basis of disease and developing novel disease modifying OA therapies. Because ... ...

    Abstract Given the prevalence and the scope of the personal and societal burden of osteoarthritis (OA), investigators continue to be deeply interested in understanding the pathogenic basis of disease and developing novel disease modifying OA therapies. Because joint trauma/injury is considered a leading predisposing factor in the development of OA, and since posttraumatic OA is one of the most common forms of OA in general, large animal and rodent models of knee injury that accurately recapitulate the OA disease process have become increasingly widespread over the past decade. To enable study in the context of defined genetic backgrounds, investigative teams have developed standardized protocols for injuring the mouse knee that aim to induce a reproducible degenerative process both in terms of severity and temporal pacing of disease progression. The destabilization of the medial meniscus (DMM) is one of the most commonly employed surgical procedure in rodents that reproducibly models posttraumatic OA and allows for the study of disease progression from initiation to end-stage disease. The description provided here sets the stage for both inexperienced and established investigators to employ the DMM procedure, or other similar surgical destabilization methods, to initiate the development of posttraumatic OA in the mouse. Successful application of this method provides a preclinical platform to study the mechanisms driving the pathogenesis of posttraumatic OA and for testing therapeutic strategies to treat it.
    MeSH term(s) Animals ; Cartilage, Articular/growth & development ; Disease Models, Animal ; Disease Progression ; Humans ; Knee Injuries/physiopathology ; Knee Injuries/surgery ; Knee Joint/physiopathology ; Knee Joint/surgery ; Menisci, Tibial/physiopathology ; Menisci, Tibial/surgery ; Mice ; Osteoarthritis/physiopathology ; Osteoarthritis/surgery
    Language English
    Publishing date 2020-11-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1028-2_6
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  4. Article ; Online: Potential causal role of synovial complement system activation in the development of post-traumatic osteoarthritis after anterior cruciate ligament injury or meniscus tear.

    Holers, V Michael / Frank, Rachel M / Clauw, Andrew / Seifert, Jennifer / Zuscik, Michael / Asokan, Sakthi / Striebich, Christopher / Clay, Michael R / Moreland, Larry W / Banda, Nirmal K

    Frontiers in immunology

    2023  Volume 14, Page(s) 1146563

    Abstract: Anterior cruciate ligament (ACL) injury and meniscal tear (MT) are major causal factors for developing post-traumatic osteoarthritis (PTOA), but the biological mechanism(s) are uncertain. After these structural damages, the synovium could be affected by ... ...

    Abstract Anterior cruciate ligament (ACL) injury and meniscal tear (MT) are major causal factors for developing post-traumatic osteoarthritis (PTOA), but the biological mechanism(s) are uncertain. After these structural damages, the synovium could be affected by complement activation that normally occurs in response to tissue injury. We explored the presence of complement proteins, activation products, and immune cells, in discarded surgical synovial tissue (DSST) collected during arthroscopic ACL reconstructive surgery, MT-related meniscectomy and from patients with OA. Multiplexed immunohistochemistry (MIHC) was used to determine the presence of complement proteins, receptors and immune cells from ACL, MT, OA synovial tissue vs. uninjured controls. Examination of synovium from uninjured control tissues did not reveal the presence of complement or immune cells. However, DSST from patients undergoing ACL and MT repair demonstrated increases in both features. In ACL DSST, a significantly higher percentage of C4d+, CFH+, CFHR4+ and C5b-9+ synovial cells were present compared with MT DSST, but no major differences were seen between ACL and OA DSST. Increased cells expressing C3aR1 and C5aR1, and a significant increase in mast cells and macrophages, were found in ACL as compared to MT synovium. Conversely, the percentage of monocytes was increased in the MT synovium. Our data demonstrate that complement is activated in the synovium and is associated with immune cell infiltration, with a more pronounced effect following ACL as compared to MT injury. Complement activation, associated with an increase in mast cells and macrophages after ACL injury and/or MT, may contribute to the development of PTOA.
    MeSH term(s) Humans ; Anterior Cruciate Ligament Injuries/complications ; Anterior Cruciate Ligament Injuries/surgery ; Osteoarthritis, Knee/etiology ; Arthroplasty, Replacement, Knee/adverse effects ; Complement Activation ; Meniscus/surgery
    Language English
    Publishing date 2023-05-03
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1146563
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  5. Article ; Online: Pharmacological Attenuation of Electrical Effects in a Model of Compression Neuropathy.

    Modrak, Maxwell / Sundem, Leigh / Gupta, Ranjan / Zuscik, Michael J / Elfar, John

    The Journal of bone and joint surgery. American volume

    2019  Volume 101, Issue 6, Page(s) 523–530

    Abstract: Background: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin ( ...

    Abstract Background: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression.
    Methods: Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis.
    Results: During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals.
    Conclusions: Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice.
    Clinical relevance: Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.
    MeSH term(s) 4-Aminopyridine/therapeutic use ; Animals ; Decompression, Surgical ; Disease Models, Animal ; Epoetin Alfa/therapeutic use ; Hematinics/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Compression Syndromes/physiopathology ; Nerve Compression Syndromes/therapy ; Neural Conduction/physiology ; Potassium Channel Blockers/therapeutic use ; Sciatic Neuropathy/physiopathology ; Sciatic Neuropathy/therapy
    Chemical Substances Hematinics ; Potassium Channel Blockers ; Epoetin Alfa (64FS3BFH5W) ; 4-Aminopyridine (BH3B64OKL9)
    Language English
    Publishing date 2019-03-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 220625-0
    ISSN 1535-1386 ; 0021-9355
    ISSN (online) 1535-1386
    ISSN 0021-9355
    DOI 10.2106/JBJS.18.00162
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  6. Article ; Online: Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis.

    Carlson, Elijah L / Karuppagounder, Vengadeshprabhu / Pinamont, William J / Yoshioka, Natalie K / Ahmad, Adeel / Schott, Eric M / Le Bleu, Heather K / Zuscik, Michael J / Elbarbary, Reyad A / Kamal, Fadia

    Science translational medicine

    2021  Volume 13, Issue 580

    Abstract: Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. ...

    Abstract Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)-approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.
    MeSH term(s) Animals ; Cartilage ; Cartilage, Articular ; Chondrocytes ; G-Protein-Coupled Receptor Kinase 2 ; Mice ; Osteoarthritis/drug therapy ; Paroxetine/pharmacology ; Paroxetine/therapeutic use
    Chemical Substances Paroxetine (41VRH5220H) ; G-Protein-Coupled Receptor Kinase 2 (EC 2.7.11.16)
    Language English
    Publishing date 2021-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.aau8491
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    Zs.A 6941: Show issues Location:
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  7. Article ; Online: The gut microbiome-joint connection: implications in osteoarthritis.

    Favazzo, Lacey J / Hendesi, Honey / Villani, David A / Soniwala, Sarah / Dar, Qurratul-Ain / Schott, Eric M / Gill, Steven R / Zuscik, Michael J

    Current opinion in rheumatology

    2019  Volume 32, Issue 1, Page(s) 92–101

    Abstract: Purpose of review: Osteoarthritis is a debilitating disease leading to joint degeneration, inflammation, pain, and disability. Despite efforts to develop a disease modifying treatment, the only accepted and available clinical approaches involve ... ...

    Abstract Purpose of review: Osteoarthritis is a debilitating disease leading to joint degeneration, inflammation, pain, and disability. Despite efforts to develop a disease modifying treatment, the only accepted and available clinical approaches involve palliation. Although many factors contribute to the development of osteoarthritis, the gut microbiome has recently emerged as an important pathogenic factor in osteoarthritis initiation and progression. This review examines the literature to date regarding the link between the gut microbiome and osteoarthritis.
    Recent findings: Studies showing correlations between serum levels of bacterial metabolites and joint degeneration were the first links connecting a dysbiosis of the gut microbiome with osteoarthritis. Further investigations have demonstrated that microbial community shifts induced by antibiotics, a germ-free environment or high-fat are important underlying factors in joint homeostasis and osteoarthritis. It follows that strategies to manipulate the microbiome have demonstrated efficacy in mitigating joint degeneration in osteoarthritis. Moreover, we have observed that dietary supplementation with nutraceuticals that are joint protective may exert their influence via shifts in the gut microbiome.
    Summary: Although role of the microbiome in osteoarthritis is an area of intense study, no clear mechanism of action has been determined. Increased understanding of how the two factors interact may provide mechanistic insight into osteoarthritis and lead to disease modifying treatments.
    MeSH term(s) Dysbiosis/complications ; Dysbiosis/metabolism ; Dysbiosis/microbiology ; Gastrointestinal Microbiome/physiology ; Humans ; Inflammation/metabolism ; Inflammation/microbiology ; Osteoarthritis/metabolism ; Osteoarthritis/microbiology
    Language English
    Publishing date 2019-11-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 1045317-9
    ISSN 1531-6963 ; 1040-8711
    ISSN (online) 1531-6963
    ISSN 1040-8711
    DOI 10.1097/BOR.0000000000000681
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    Zs.A 3028: Show issues Location:
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  8. Article ; Online: Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice.

    Catheline, Sarah E / Hoak, Donna / Chang, Martin / Ketz, John P / Hilton, Matthew J / Zuscik, Michael J / Jonason, Jennifer H

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2019  Volume 34, Issue 9, Page(s) 1676–1689

    Abstract: RUNX2 is a transcription factor critical for chondrocyte maturation and normal endochondral bone formation. It promotes the expression of factors catabolic to the cartilage extracellular matrix and is upregulated in human osteoarthritic cartilage and in ... ...

    Abstract RUNX2 is a transcription factor critical for chondrocyte maturation and normal endochondral bone formation. It promotes the expression of factors catabolic to the cartilage extracellular matrix and is upregulated in human osteoarthritic cartilage and in murine articular cartilage following joint injury. To date, in vivo studies of RUNX2 overexpression in cartilage have been limited to forced expression in osteochondroprogenitor cells preventing investigation into the effects of chondrocyte-specific RUNX2 overexpression in postnatal articular cartilage. Here, we used the Rosa26
    MeSH term(s) Aging/pathology ; Animals ; Animals, Newborn ; Cartilage, Articular/pathology ; Chondrocytes/metabolism ; Chondrocytes/pathology ; Core Binding Factor Alpha 1 Subunit/metabolism ; Disease Progression ; Female ; Humans ; Knee Joint/pathology ; Male ; Matrix Metalloproteinase 13/metabolism ; Mice ; Organ Specificity ; Osteoarthritis/etiology ; Osteoarthritis/metabolism ; Osteochondrodysplasias/pathology ; Phenotype ; Wounds and Injuries/complications
    Chemical Substances Core Binding Factor Alpha 1 Subunit ; Runx2 protein, mouse ; Matrix Metalloproteinase 13 (EC 3.4.24.-)
    Language English
    Publishing date 2019-06-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.3737
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  9. Article ; Online: IKKβ-NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice.

    Catheline, Sarah E / Bell, Richard D / Oluoch, Luke S / James, M Nick / Escalera-Rivera, Katherine / Maynard, Robert D / Chang, Martin E / Dean, Christopher / Botto, Elizabeth / Ketz, John P / Boyce, Brendan F / Zuscik, Michael J / Jonason, Jennifer H

    Science signaling

    2021  Volume 14, Issue 701, Page(s) eabf3535

    Abstract: Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, ...

    Abstract Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase β (IKKβ) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKβ had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1β (IL-1β) in vitro, the loss of p50 enhanced the IL-1β–induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKβ activation. Overall, our data reveal that IKKβ-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.
    MeSH term(s) Animals ; Chondrocytes/metabolism ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Mice ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Osteoarthritis/genetics ; Signal Transduction
    Chemical Substances NF-kappa B ; I-kappa B Kinase (EC 2.7.11.10)
    Language English
    Publishing date 2021-09-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.abf3535
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  10. Article ; Online: Attenuated Joint Tissue Damage Associated With Improved Synovial Lymphatic Function Following Treatment With Bortezomib in a Mouse Model of Experimental Posttraumatic Osteoarthritis.

    Wang, Wensheng / Lin, Xi / Xu, Hao / Sun, Wen / Bouta, Echoe M / Zuscik, Michael J / Chen, Di / Schwarz, Edward M / Xing, Lianping

    Arthritis & rheumatology (Hoboken, N.J.)

    2019  Volume 71, Issue 2, Page(s) 244–257

    Abstract: Objective: To investigate the roles of the synovial lymphatic system in the severity and progression of joint tissue damage and functional responses of synovial lymphatic endothelial cells (LECs) to macrophage subsets, and to evaluate the therapeutic ... ...

    Abstract Objective: To investigate the roles of the synovial lymphatic system in the severity and progression of joint tissue damage and functional responses of synovial lymphatic endothelial cells (LECs) to macrophage subsets, and to evaluate the therapeutic potential of the proteasome inhibitor bortezomib (BTZ) in a mouse model of experimental posttraumatic osteoarthritis (OA).
    Methods: C57BL/6J wild-type mice received a meniscal ligamentous injury to induce posttraumatic knee OA. Lymphangiogenesis was blocked by a vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody. Synovial lymphatic drainage was examined by near-infrared imaging. Joint damage was assessed by histology. RNA-sequencing and pathway analyses were applied to synovial LECs. Macrophage subsets in the mouse synovium were identified by flow cytometry and immunofluorescence staining. M1 and M2 macrophages were induced from mouse bone marrow cells, and their effects on LECs were examined in cocultures in the presence or absence of BTZ. The effects of BTZ on joint damage, LEC inflammation, and synovial lymphatic drainage were examined.
    Results: Injection of a VEGFR-3 neutralizing antibody into the joints of mice with posttraumatic knee OA reduced synovial lymphatic drainage and accelerated joint tissue damage. Synovial LECs from the mouse OA joints had dysregulated inflammatory pathways and expressed high levels of inflammatory genes. The number of M1 macrophages was increased in the knee joints of mice with posttraumatic OA, thereby promoting the expression of inflammatory genes by LECs; this effect was blocked by BTZ. Treatment with BTZ decreased cartilage loss, reduced the expression of inflammatory genes by LECs, and improved lymphatic drainage in the knee joints of mice with posttraumatic OA.
    Conclusion: Experimental posttraumatic knee OA is associated with decreased synovial lymphatic drainage, increased numbers of M1 macrophages, and enhanced inflammatory gene expression by LECs, all of which was improved by treatment with BTZ. Intraarticular administration of BTZ may represent a new therapy for the restoration of synovial lymphatic function in subjects with posttraumatic knee OA.
    MeSH term(s) Animals ; Antibodies, Neutralizing/pharmacology ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Coculture Techniques ; Disease Progression ; Endothelial Cells/drug effects ; Inflammation ; Knee Injuries/complications ; Lymphangiogenesis/drug effects ; Lymphatic Vessels/drug effects ; Lymphatic Vessels/immunology ; Macrophages/drug effects ; Macrophages/immunology ; Mice ; Osteoarthritis, Knee/drug therapy ; Osteoarthritis, Knee/etiology ; Osteoarthritis, Knee/immunology ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use ; Spectroscopy, Near-Infrared ; Synovial Membrane/drug effects ; Vascular Endothelial Growth Factor Receptor-3/antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-3/immunology
    Chemical Substances Antibodies, Neutralizing ; Proteasome Inhibitors ; Bortezomib (69G8BD63PP) ; Vascular Endothelial Growth Factor Receptor-3 (EC 2.7.10.1)
    Language English
    Publishing date 2019-01-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.40696
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