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Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP).
Bone. 2018 04; 109:218-224.BONE

Abstract

BACKGROUND

Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking.

OBJECTIVE

To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H).

RESULTS

We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling.

CONCLUSIONS

The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP.

Authors+Show Affiliations

Department of Physiology and Biomedical Engineering, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address: Wang.Haitao@mayo.edu.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: shore@mail.med.upenn.edu.Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address: pignolo.robert@mayo.edu.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: frederick.kaplan@uphs.upenn.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29170109

Citation

Wang, Haitao, et al. "Activin a Amplifies Dysregulated BMP Signaling and Induces Chondro-osseous Differentiation of Primary Connective Tissue Progenitor Cells in Patients With Fibrodysplasia Ossificans Progressiva (FOP)." Bone, vol. 109, 2018, pp. 218-224.
Wang H, Shore EM, Pignolo RJ, et al. Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone. 2018;109:218-224.
Wang, H., Shore, E. M., Pignolo, R. J., & Kaplan, F. S. (2018). Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone, 109, 218-224. https://doi.org/10.1016/j.bone.2017.11.014
Wang H, et al. Activin a Amplifies Dysregulated BMP Signaling and Induces Chondro-osseous Differentiation of Primary Connective Tissue Progenitor Cells in Patients With Fibrodysplasia Ossificans Progressiva (FOP). Bone. 2018;109:218-224. PubMed PMID: 29170109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). AU - Wang,Haitao, AU - Shore,Eileen M, AU - Pignolo,Robert J, AU - Kaplan,Frederick S, Y1 - 2017/11/21/ PY - 2017/09/16/received PY - 2017/11/17/revised PY - 2017/11/18/accepted PY - 2017/11/25/pubmed PY - 2018/11/20/medline PY - 2017/11/25/entrez KW - ACVR1 KW - Activin A KW - Bone morphogenetic protein (BMP) KW - Bone morphogenetic protein signaling KW - Fibrodysplasia ossificans progressiva (FOP) KW - Heterotopic ossification SP - 218 EP - 224 JF - Bone JO - Bone VL - 109 N2 - BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. OBJECTIVE: To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). RESULTS: We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. CONCLUSIONS: The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/29170109/Activin_A_amplifies_dysregulated_BMP_signaling_and_induces_chondro_osseous_differentiation_of_primary_connective_tissue_progenitor_cells_in_patients_with_fibrodysplasia_ossificans_progressiva__FOP__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30433-7 DB - PRIME DP - Unbound Medicine ER -