The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva

Zhengqin Ye; Siyi Wang; Chang Shan; Qi Zhu; Ying Xue; Keqin Zhang

doi:10.1186/s13023-023-02708-3

The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva

Orphanet J Rare Dis. 2023 May 10;18(1):111. doi: 10.1186/s13023-023-02708-3.

Authors

Zhengqin Ye^#¹, Siyi Wang^#², Chang Shan¹, Qi Zhu¹, Ying Xue¹, Keqin Zhang^{3

4}

Affiliations

¹ Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, China.
² Medical School of Nantong University, Affiliated Hospital of Nantong University, 19 Qixiu Road, Nantong, Jiangsu, China.
³ Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, China. keqzhang2007@126.com.
⁴ Institute of Osteoporosis and Metabolic Bone Diseases, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, China. keqzhang2007@126.com.

^# Contributed equally.

Abstract

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients.

Results: We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients.

Conclusions: There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.

Keywords: Activin A; Bone morphogenetic protein 4 (BMP4); Bone morphogenetic protein 6 (BMP6); Fibrodysplasia ossificans progressiva (FOP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism
Animals
Bone Morphogenetic Proteins / genetics
Bone Morphogenetic Proteins / metabolism
Mice
Mutation
Myositis Ossificans* / genetics
Ossification, Heterotopic* / genetics
Retrospective Studies

Substances

activin A
Bone Morphogenetic Proteins
Activin Receptors, Type I