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Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification.
Stem Cells. 2014 May; 32(5):1289-300.SC

Abstract

Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder fibrodysplasia ossificans progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2(R206H/+) (gain-of-function), Alk2(CKO) (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2(R206H/+) cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2(R206H/+) cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2(CKO) cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions.

Authors+Show Affiliations

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24449086

Citation

Culbert, Andria L., et al. "Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification." Stem Cells (Dayton, Ohio), vol. 32, no. 5, 2014, pp. 1289-300.
Culbert AL, Chakkalakal SA, Theosmy EG, et al. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014;32(5):1289-300.
Culbert, A. L., Chakkalakal, S. A., Theosmy, E. G., Brennan, T. A., Kaplan, F. S., & Shore, E. M. (2014). Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells (Dayton, Ohio), 32(5), 1289-300. https://doi.org/10.1002/stem.1633
Culbert AL, et al. Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification. Stem Cells. 2014;32(5):1289-300. PubMed PMID: 24449086.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. AU - Culbert,Andria L, AU - Chakkalakal,Salin A, AU - Theosmy,Edwin G, AU - Brennan,Tracy A, AU - Kaplan,Frederick S, AU - Shore,Eileen M, PY - 2013/08/06/received PY - 2013/11/25/revised PY - 2013/12/11/accepted PY - 2014/1/23/entrez PY - 2014/1/23/pubmed PY - 2014/12/17/medline KW - Alk2 KW - Bone morphogenetic protein signaling KW - Chondrogenesis KW - Endochondral ossification KW - Fibrodysplasia ossificans progressiva SP - 1289 EP - 300 JF - Stem cells (Dayton, Ohio) JO - Stem Cells VL - 32 IS - 5 N2 - Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder fibrodysplasia ossificans progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2(R206H/+) (gain-of-function), Alk2(CKO) (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2(R206H/+) cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2(R206H/+) cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2(CKO) cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions. SN - 1549-4918 UR - https://www.unboundmedicine.com/medline/citation/24449086/Alk2_regulates_early_chondrogenic_fate_in_fibrodysplasia_ossificans_progressiva_heterotopic_endochondral_ossification_ L2 - https://doi.org/10.1002/stem.1633 DB - PRIME DP - Unbound Medicine ER -