Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age-Related Osteoarthritis in Mice.

Autor: Lin X; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York., Bell RD; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York., Catheline SE; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York., Takano T; Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York., McDavid A; Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York., Jonason JH; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York., Schwarz EM; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York., Xing L; Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 Jun; Vol. 75 (6), pp. 923-936. Date of Electronic Publication: 2023 Apr 17.
DOI: 10.1002/art.42441
Abstrakt: Objective: The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease.
Methods: SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints.
Results: Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T 1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P = 0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[μW/cm 2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P = 0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm 2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm 2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P = 0.0004).
Conclusion: SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.
(© 2023 American College of Rheumatology.)
Databáze: MEDLINE
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