Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP)

Abstract

Background: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies.

Results: Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions.

Conclusions: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition.

Keywords: ACVR1; Cromolyn; Fibrodyplasia ossificans progressiva (FOP); Heterotopic ossification; Mast cells.

Fig. 1.

Aprepitant does not reduceHOina caACVR1 mouse model of FOP. (A) Representative examples of HO formation by μCT. (B) Quantification of HO volume among the treatment doses of aprepitant.

Fig. 2.

Cromolyn effectively reduces HO in a caACVR1 mouse model of FOP. (A) Representative examples of HO formation by μCT. (B) Quantification of HO volume between the treatment groups. *, p < 0.05.

Fig. 3.

Mast cell subtypes in early injury-induced lesions in a caACVR1 mouse model of FOP (day 2 after injury). Note the broken membrane and release of granules in activated (DG) mast cells. RG, resting granulated; DG, degranulating; RD, resting degranulated (RD).

Fig. 4.

Quantification of total mast cells (A) and mast cell subtypes (B) in control caACVR1 mice. Data is shown for days two, five, and seven after muscle injury. D, day.

Fig. 5.

Total mast cell number isreduced in cromolyn- but not aprepitant-treated caACVR1 mice. Data shown is for day five after injury induction. *, p < 0.05.

Fig. 6.

Quantification of mast cell subtypes in cromolyn-treated caACVR1 mice. Data is shown for days two, five, and seven after muscle injury. *, p < 0.5; **, p < 0.01; D, day.

Fig. 7.

Schema showing cellular mechanisms of mast cell inhibition by cromolyn. Note that cromolyn antagonizes both the activation of mast cells (DG) from RG cells as well as the production of RD cells, preventing the regeneration of RG cells. Cromolyn may also act by directly inhibiting or removing DG and RG cells from the regeneration cycle. RG, resting granulated; DG, degranulating; RD, resting degranulated (RD).