Mast Cells Enhance Sterile Inflammation in Chronic Nonbacterial Osteomyelitis

Abstract

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease. While some patients exhibit bone lesions at single sites, most patients develop chronically active or recurrent bone inflammation at multiple sites, and are then diagnosed with recurrent multifocal osteomyelitis (CRMO). Chronic multifocal osteomyelitis (CMO) mice develop IL-1β-driven sterile bone lesions reminscent of severe CRMO. Mechanistically, CMO disease arises due to loss of PSTPIP2, a negative regulator of macrophages, osteoclasts and neutrophils. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO disease pathophysiology. Here, we show that mast cells accumulate in the inflamed tissues from CMO mice, and mast cell protease Mcpt1 was detected in the peripheral blood. The role of mast cells in CMO disease was investigated using a transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) that was crossed with CMO mice. The resulting CMO/MC-mice showed a significant delay in disease onset compared to age-matched CMO mice. At 5-6 months of age, CMO/MC- mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tail and paw tissues. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls or CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as patients with oligoclonal juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients as well as patients with bacterial osteomyelitis. Taken together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO. Observations of this study promise potential for mast cells and derived mediators as future biomarkers and/or therapeutic targets.

Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO)

“…In turn, mast cell-deficient animals exhibit attenuated disease suggesting their direct contribution or (at least) amplification of inflammation through mast cells. This is in line with the presence of mast cells and neutrophils in bone biopsies from children with CNO/CRMO and elevated levels of mast cell chymase in their peripheral blood [ 109 ].…”

“…Src kinase inhibition in patients with FGR mutations) [ 96 ]. The involvement of mast cells in bone inflammation may result in trials testing mast cell inhibitors in CNO/CRMO to control disease [ 109 ]. While studies available delivered individual proteins or pathways that are dysregulated in CNO/CRMO, therapeutic applications arising cannot be predicted with certainty.…”