Critical role of the mast cell/tryptase/PAR2 axis in anastrozole-induced pain

Anastrozole, an aromatase inhibitor, is used to treat postmenopausal women with hormone receptor-positive breast cancer, but also induces musculoskeletal pain and can lead to therapeutic regimen suspension. Aromatase inhibitors promote the release of pro-inflammatory substances from sensitised nerve fibres, which might lead to peripheral mast cell activation.

We explore if tryptase released by peripheral mast cells could activate the protease-activated receptor 2 (PAR2) to sustain anastrozole-induced painful symptoms.

Anastrozole caused mechanical allodynia, muscle strength loss, and increased mast cell number and tryptase levels in the plantar tissue of male C57BL/6 mice. Depletion (using compound 48/80) or stabilisation (using ketotifen fumarate) of mast cells prevented anastrozole-induced mechanical allodynia and muscle strength loss. Compound 48/80 also prevented the increase in the number of mast cells in the plantar tissue. Tryptase inhibitors nafamostat and gabexate, or PAR2 inhibitors ENMD-1068 and AZ3451, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. Furthermore, anastrozole did not cause mechanical allodynia and muscle strength loss in global (PAR2^-/-) or sensory neuron-specific (PAR2 Na_v 1.8^-/-) PAR2 knockout mice. Local sub-nociceptive doses of the PAR2 agonists (tryptase, trypsin or 2F) enhanced the anastrozole-induced mechanical sensitivity in wild-type mice, which was reduced by pre-treatment with AZ3451. PAR2^-/- or PAR2 Na_v 1.8^-/- mice treated with anastrozole did not respond to local sub-nociceptive doses of PAR2 agonists.

Our results provide a new mechanism underlying anastrozole-induced pain, highlighting the mast cell/tryptase/PAR2 axis as a therapeutic target to manage painful symptoms.