Vasoinhibin reduces joint inflammation, bone loss, and the angiogenesis and vasopermeability of the pannus in murine antigen-induced arthritis

Increased permeability and growth (angiogenesis) of blood vessels play a key role in joint swelling and pannus formation in inflammatory arthritis, a family of diseases influenced by reproductive hormones. The hormone prolactin (PRL) protects against joint inflammation, pannus formation, and bone de...

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Bibliographic Details
Published in:Laboratory investigation 2020-08, Vol.100 (8), p.1068-1079
Main Authors: Ortiz, Georgina, Ledesma-Colunga, Maria G., Wu, Zhijian, García-Rodrigo, Jose F., Adan, Norma, Martínez de la Escalera, Gonzalo, Clapp, Carmen
Format: Article
Language:English
Subjects:
Activation
Angiogenesis
Animals
Antigens
Arthritis
Arthritis, Experimental - chemically induced
Arthritis, Experimental - genetics
Arthritis, Experimental - therapy
Blood vessels
Bone growth
Bone loss
Capillary Permeability - drug effects
Cell adhesion
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cytokines
Dependovirus - genetics
Endothelial cells
Gene therapy
Gene transfer
Genetic Therapy - methods
Genetic Vectors - genetics
Growth factors
Hormones
Humans
Hyperplasia
Hypoxia
Hypoxia-inducible factor 1a
Hypoxia-inducible factors
IL-1β
Inflammation
Injection
Interleukin 6
Interleukins
Joints (anatomy)
Joints - pathology
Male
Mice, Inbred C57BL
Nitric oxide
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
Nitric-oxide synthase
Osteitis - genetics
Osteitis - prevention & control
Osteitis - therapy
Osteoporosis - genetics
Osteoporosis - prevention & control
Osteoporosis - therapy
Permeability
Phosphorylation
Prolactin
Prolactin - pharmacology
Proteolysis
Vascular endothelial growth factor
Viruses
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Summary:Increased permeability and growth (angiogenesis) of blood vessels play a key role in joint swelling and pannus formation in inflammatory arthritis, a family of diseases influenced by reproductive hormones. The hormone prolactin (PRL) protects against joint inflammation, pannus formation, and bone destruction in adjuvant-induced arthritis and these effects may involve its proteolytic conversion to vasoinhibin, a PRL fragment that inhibits angiogenesis and vasopermeability. Here, we show that the intra-articular injection of an adeno-associated virus type-2 (AAV2) vector encoding vasoinhibin reduced joint inflammation, the hyperplasia, vascular density, and vasopermeability of the pannus, and the loss of bone in mice subjected to antigen-induced arthritis. In agreement, the AAV2 vasoinhibin vector reduced the expression of proinflammatory cytokines (interleukin-1β, interleukin-6), an endothelial cell marker (platelet endothelial cell-adhesion molecule 1), and proangiogenic molecules [vascular endothelial growth factor (VEGF), VEGF receptor 2, and hypoxia-inducible factor 1α] in the arthritic joint. Also, vasoinhibin reduced the synovial vasopermeability induced by the intra-articular injection of VEGF in healthy mice. Finally, vasoinhibin signals by blocking the phosphorylation/activation of endothelial nitric oxide synthase (eNOS) at Ser1179 and the AAV2 vasoinhibin vector inhibited the enhanced phosphorylation of eNOS Ser1179 in the arthritic joint. We conclude that vasoinhibin reduces joint inflammation and bone loss in arthritis by inhibiting pannus angiogenesis and vasopermeability via the blockage of VEGF-induced eNOS activation. These findings suggest the potential therapeutic benefit of AAV2-mediated vasoinhibin gene delivery in arthritis. Adeno-associated virus type 2 encoding the prolactin fragment vasoinhibin (AAV2 vasoinhibin) reduces joint inflammation and bone loss in antigen-induced arthritis in mice by inhibiting pannus angiogenesis and vasopermeability via the blockage of VEGF-induced eNOS activation. These findings suggest the potential benefit of vasoinhibin gene therapy in arthritis.
ISSN:0023-6837
1530-0307
DOI:10.1038/s41374-020-0432-5