BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP)

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease caused by increased BMP pathway signaling due to mutation of ACVR1, a bone morphogenetic protein (BMP) type 1 receptor. The primary clinical manifestation of FOP is extra-skeletal bone formation (heterotopic ossification) within soft connective tissues. However, the underlying ACVR1 mutation additionally alters skeletal bone development and nearly all people born with FOP have bilateral malformation of the great toes as well as other skeletal malformations at diverse anatomic sites. The specific mechanisms through which ACVR1 mutations and altered BMP pathway signaling in FOP influence skeletal bone formation during development remain to be elucidated; however, recent investigations are providing a clearer understanding of the molecular and developmental processes associated with ACVR1-regulated skeletal formation.

Keywords: ACVR1; FOP; bone morphogenetic protein; fibrodysplasia ossificans progressiva; heterotopic ossification; joint development; toe/digit malformation.

FIGURE 1

Disruption of joint development due to mutations in the BMP signaling pathway. A, Long bones of the limb begin as rod-like regions of pre-cartilaginous condensed mesenchyme that express Sox9 as they undergo chondrogenic differentiation (approximately E12.0 in mouse digits). Acvr1 expression is diffuse within this pre-cartilage. B, At intervals long these “rods,” expression of antagonists of BMP-pSmad1/5 signaling generates joint interzones (left). Gdf5+ cells migrate from the periphery of these regions into the interzone, where they begin to differentiate into joint tissues (approximately E13.0 in mouse digits). When BMP signaling is disrupted (increased) in one or more ways (as in Gdf5^−/−, Bmpr1b^−/−, Acvr1^R206H/+ tissues, for example), Gdf5+ cells are unable to invade the interzone (right). By this time, Acvr1 expression is restricted to the outer perichondrium and growth plate in control animals, but has not been examined in mice carrying these mutations. C, Once the mature joint is formed, a regulated balance of TGFß, Wnt, and BMP signaling maintains healthy articular cartilage and other joint tissues through development and into adult life (left). Consequently, disrupting the initial patterning of joint tissues leads to impaired or absent joint formation, poor joint and articular cartilage tissue maintenance, increased susceptibility to degeneration, and reduced joint function (right)

FIGURE 2

Altered hindlimb digit patterning due to mutations in the BMP signaling pathway. Schematic drawings illustrate key features of human (A-D) and mouse (E-H) digits. A, The typical arrangement of human feet includes five digits (1–5). The first digit only has three primary ossification centers (POCs; white), which give rise to one metatarsal (mt) and two phalanges (p1 and p2), whereas digits 2 to 5 have a metatarsal and three phalanges each (p1–p3). In humans, every POC may have an associated secondary ossification center (SOC, gray), although the total number of SOCs in an individual is variable in the general population. B, B′ The FOP ACVR1^R206H digit phenotype, with the first digit at an angle from the other digits (hallux valgus deformity), may or may not include a proximal phalanx, includes an ectopic ossification center distal to the first metatarsal (blue), often has positionally deviated sesamoids (black), and may include longitudinal epiphyseal bracket (illustrated in B′). C, An atypical human FOP mutation in ACVR1, G328E, is associated with loss of all distal phalanges, loss of the proximal phalanx, and fusion between metatarsals 3 and 4. D, A deletion in the gene encoding BMPR1B in one human patient was associated with an FOP-like phenotype. Sesamoids and SOCs could not be conclusively assessed due to the young age of the subject. E, In mice, each POC except the third phalanx on each digit has an associated SOC and each metatarsal has two sesamoids. F, In mice expressing Acvr1^R206H/+ (induced by Prrx1-Cre), the first metatarsophalangeal joint (mt-p1) can fuse partially or entirely, sesamoid bones are fused, and an extra skeletal element connects to the usual anatomy via a longitudinal growth plate. Mice expressing this mutation additionally lose the medial phalanx of digits 2 and 5 and show mt-p1 fusion in digit 5. G, Conditional knockout of Acvr1 using Prrx1-Cre in mice causes loss of the proximal phalanx in digit 1, reduced length of all bones of the digits, and reduced joint flexibility in digits 2 to 5 (represented by reduced joint space). H, Mice with brachypodism (bp/bp) have a nearly identical appearance to FOP models, including loss of phalanges, fusion of digit sesamoids, and shortening of skeletal elements