TAT-Beclin-1 induces severe synovial hyperplasia and does not protect from injury-induced osteoarthritis in mice

J S Rockel; B Wu; S Nakamura; E Rossomacha; O Espin-Garcia; R Gandhi; M Kapoor

doi:10.1016/j.joca.2020.07.001

TAT-Beclin-1 induces severe synovial hyperplasia and does not protect from injury-induced osteoarthritis in mice

Osteoarthritis Cartilage. 2020 Oct;28(10):1394-1400. doi: 10.1016/j.joca.2020.07.001. Epub 2020 Jul 17.

Authors

J S Rockel¹, B Wu¹, S Nakamura¹, E Rossomacha¹, O Espin-Garcia², R Gandhi³, M Kapoor⁴

Affiliations

¹ Arthritis Program, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
² Arthritis Program, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
³ Arthritis Program, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
⁴ Arthritis Program, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada. Electronic address: Mohit.Kapoor@uhnresearch.ca.

PMID: 32683043
DOI: 10.1016/j.joca.2020.07.001

Abstract

Object: Autophagy maintains cartilage homeostasis and is compromised during osteoarthritis (OA), contributing to cartilage degeneration. We sought to determine if D-isomer TAT-Beclin-1, a potent inducer of autophagy, could attenuate post-traumatic OA in mice.

Methods: 10-week-old mice underwent destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA, or sham surgery (control), and injected intra-articularly with D-isomer TAT-Beclin-1 (0.5-2 mg/kg) or PBS 1 week post-surgery for up to 9 weeks. Mice were sacrificed at 2 or 10 weeks post-surgery. Knee joint sections were evaluated by histopathology for cartilage degeneration and synovitis, and immunostaining for key markers of autophagy (LC3B), cell proliferation (nuclear Ki67), activated fibroblasts (αSMA), and cells of hematopoietic origin (CD45).

Results: All D-isomer TAT-Beclin-1-treated DMM mice had no difference in the degree of cartilage degeneration compared to PBS-injected DMM mice. Surprisingly, all D-isomer TAT-Beclin-1-treated mice exhibited substantial synovial hyperplasia, with increased cellularity and ECM deposition (fibrosis-like phenotype), as compared to PBS-injected mice. Synovial effects of D-isomer TAT-Beclin-1 were dose- and injection frequency-dependent. An increased percentage of cells positive for LC3B and nuclear Ki67 were found in the synovial intima early after injection, which persisted after frequent injections.

Conclusions: D-isomer TAT-Beclin-1 did not attenuate cartilage degeneration, but rather induced synovial hyperplasia associated with increased expression of key markers of autophagy and cell proliferation and a fibrosis-like phenotype, independent of markers of fibroblast activation or persistent hematopoietic-origin cell infiltration. These data suggest that, if not tissue-targeted, caution should be taken using autophagy activators due to diverse cellular responses in the joint.

Keywords: Autophagy; Cartilage; Meniscus; Proliferation; Synovium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / drug effects*
Beclin-1 / pharmacology*
Cartilage, Articular / drug effects*
Cartilage, Articular / pathology
Cell Proliferation / drug effects*
Disease Models, Animal
Fibroblasts / drug effects
Gene Products, tat / pharmacology
Hyperplasia
Injections, Intra-Articular
Menisci, Tibial / surgery
Mice
Osteoarthritis, Knee / pathology*
Synovial Membrane / drug effects*
Synovial Membrane / pathology
Synovitis / pathology
Tibial Meniscus Injuries

Substances

Beclin-1
Gene Products, tat

Grants and funding

FRN: 153218/CIHR/Canada