Do Interactions of Vitamin D3 and BMP Signaling Hold Implications in the Pathogenesis of Fibrodysplasia Ossificans Progressiva?

Abstract

Purpose of review: Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in ACVR1/ALK2. However, disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D₃ in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D's effects in FOP by exploring relevant intersections of VD₃ with mechanisms of FOP flares.

Recent findings: In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D₃ protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP. There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.

Keywords: ALK2; Chondrogenesis; Inflammation; Muscle repair; Skeletal muscle; VDR.

Fig. 1

Potential effects of vitamin D₃ (VD₃) on known mechanisms in FOP. The high-affinity binding of Activin A (ActA) to ALK2^R206H induces kinase activity, Smad1/5/8 phosphorylation, translocation, and transcriptional activity to drive inflammatory, chondrogenic, and osteogenic processes leading to endochondral HO in skeletal muscles of FOP patients and mice. VD₃ binds and activates either of its receptors, protein disulfide isomerase family A member 3 (Pdia3) or classical vitamin D receptor (VDR). In other experimental systems, this has been shown to enhance Smad1/5/8 signaling, chondrogenic and osteogenic differentiation, and production of ActA, processes that drive endochondral heterotopic ossification in FOP. However, VD₃ also inhibits innate inflammatory processes thought to be an important step in pathophysiology of endochondral HO, further highlighting the potential complex relationships of VD₃ with mechanisms driving FOP