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Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients.
Bone. 2021 Apr 27; 149:115978.BONE

Abstract

Progressive heterotopic ossification (HO) is a hallmark of fibrodysplasia ossificans progressiva (FOP); however, this tissue transformation is not random. Rather, we noticed that HO in FOP progresses in well-defined but inexplicable spatial and temporal patterns that correlate precisely with infrared thermographs of the human body. FOP is caused by gain-of-function mutations in Activin A receptor type I (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor kinase. As with all enzymes, the activity of ACVR1 is temperature-dependent. We hypothesized that connective tissue progenitor cells that express the common heterozygous ACVR1R206H mutation (FOP CTPCs) exhibit a dysregulated temperature response compared to control CTPCs and that the temperature of FOP CTPCs that initiate and sustain HO at various anatomic sites determines, in part, the anatomic distribution of HO in FOP. We compared BMP pathway signaling at a range of physiologic temperatures in primary CTPCs isolated from FOP patients (n = 3) and unaffected controls (n = 3) and found that BMP pathway signaling and resultant chondrogenesis were amplified in FOP CTPCs compared to control CTPCs (p < 0.05). We conclude that the anatomic distribution of HO in FOP may be due, in part, to a dyregulated temperature response in FOP CTPCs that reflect anatomic location. While the association of temperature gradients with spatial patterns of HO in FOP does not demonstrate causality, our findings provide a paradigm for the physiologic basis of the anatomic distribution of HO in FOP and unveil a novel therapeutic target that might be exploited for this disabling condition.

Authors+Show Affiliations

Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA.Department of Pediatrics, Pediatric Rheumatology Section, Hospital Italiano de Buenos Aires, Gascón 450, 1181 Ciudad Autónoma de Buenos Aires, Argentina.Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address: Pignolo.Robert@mayo.edu.Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of the Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: Frederick.Kaplan@pennmedicine.upenn.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33915334

Citation

Wang, Haitao, et al. "Spatial Patterns of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva Correlate With Anatomic Temperature Gradients." Bone, vol. 149, 2021, p. 115978.
Wang H, De Cunto CL, Pignolo RJ, et al. Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. Bone. 2021;149:115978.
Wang, H., De Cunto, C. L., Pignolo, R. J., & Kaplan, F. S. (2021). Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. Bone, 149, 115978. https://doi.org/10.1016/j.bone.2021.115978
Wang H, et al. Spatial Patterns of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva Correlate With Anatomic Temperature Gradients. Bone. 2021 Apr 27;149:115978. PubMed PMID: 33915334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. AU - Wang,Haitao, AU - De Cunto,Carmen L, AU - Pignolo,Robert J, AU - Kaplan,Frederick S, Y1 - 2021/04/27/ PY - 2020/12/23/received PY - 2021/03/23/revised PY - 2021/04/21/accepted PY - 2021/4/30/pubmed PY - 2021/4/30/medline PY - 2021/4/29/entrez KW - ACVR1 KW - ALK2 KW - BMP pathway signaling KW - Fibrodysplasia ossificans progressiva (FOP) KW - Heterotopic ossification SP - 115978 EP - 115978 JF - Bone JO - Bone VL - 149 N2 - Progressive heterotopic ossification (HO) is a hallmark of fibrodysplasia ossificans progressiva (FOP); however, this tissue transformation is not random. Rather, we noticed that HO in FOP progresses in well-defined but inexplicable spatial and temporal patterns that correlate precisely with infrared thermographs of the human body. FOP is caused by gain-of-function mutations in Activin A receptor type I (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor kinase. As with all enzymes, the activity of ACVR1 is temperature-dependent. We hypothesized that connective tissue progenitor cells that express the common heterozygous ACVR1R206H mutation (FOP CTPCs) exhibit a dysregulated temperature response compared to control CTPCs and that the temperature of FOP CTPCs that initiate and sustain HO at various anatomic sites determines, in part, the anatomic distribution of HO in FOP. We compared BMP pathway signaling at a range of physiologic temperatures in primary CTPCs isolated from FOP patients (n = 3) and unaffected controls (n = 3) and found that BMP pathway signaling and resultant chondrogenesis were amplified in FOP CTPCs compared to control CTPCs (p < 0.05). We conclude that the anatomic distribution of HO in FOP may be due, in part, to a dyregulated temperature response in FOP CTPCs that reflect anatomic location. While the association of temperature gradients with spatial patterns of HO in FOP does not demonstrate causality, our findings provide a paradigm for the physiologic basis of the anatomic distribution of HO in FOP and unveil a novel therapeutic target that might be exploited for this disabling condition. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/33915334/Spatial_patterns_of_heterotopic_ossification_in_fibrodysplasia_ossificans_progressiva_correlate_with_anatomic_temperature_gradients_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(21)00140-X DB - PRIME DP - Unbound Medicine ER -
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