Eileen M. Shore
Research Associate Professor, Depts of Orthopaedic Surgery and Genetics

Genetics and Gene Regulation Program

Address

University of Pennsylvania
Department of Orthopaedic Surgery
424 Stemmler Hall
36th and Hamilton Walk
Philadelphia, PA 19104-6081

Office tel.: 215 898-2331
Lab tel.: 215 898-5610
Fax: 215 573-2133
E-mail: shore@mail.med.upenn.edu

Link(s)

Dr Shore at the Dept of Orthopaedic Surgery

The Orthopaedic Research Lab

Education

University of Notre Dame, BS (Biology) 1976

Indiana University, MA (Biology) 1978

University of Pennsylvania, PhD (Cell and Molecular Biology) 1987

Research Interests

• Genetic Regulation of Bone Formation: Genetic diseases of bone formation and development. Molecular and cell biology of bone formation and osteoblast differentiation. Cell signaling pathways and transcriptional activation and regulation of bone morphogenetic protein (BMP) and GNAS target genes. Developmental biology of BMP signaling.

Key words: Bone formation, cell differentiation, human genetics, molecular biology, cell biology, developmental biology, gene expression, inherited diseases, bone, cartilage, bone morphogenetic protein, BMP, G-proteins, GNAS, FOP, POH.

Description of Research

Research in our laboratory is focused on genetic diseases of bone formation, mainly fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH). Both of these rare disorders are characterized by de novo formation of bone: in FOP, the ectopic bone forms in deep connective tissues such as muscle; and in POH, bone formation initiates within the skin. Our goals have been to identify the genetic causes of these conditions and the cellular pathways that are involved in the induction of bone development and formation, and to use this information to develop treatments for these and other disorders of bone.

With the identification of the mutated genes for POH and FOP, we are re-focusing our experimental directions to determine the functions of these genes and the consequences of the identified mutations. Our current work includes:

1. Genetics and epigenetics of GNAS and POH. POH is caused by heterozygous inactivating mutations in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS). Our data suggest that phenotypic expression of a GNAS mutation may be affected by genomic imprinting. GNAS is a complex gene that encodes multiple transcripts regulated by different promoters. Current studies include analysis of GNAS mRNA and protein expression and activity and examination of differentially methylated regions (DMRs) of the GNAS region.
2. The role of GNAS expression in bone cell differentiation. Ectopic bone formation in POH typically initiates within subcutaneous fat, suggesting a close relationship between osteogenesis and adipogenesis. We are using GNAS knockout mice and RNAi to study the effects of inactivation of GNAS on bone and fat cell differentiation and to examine the differential expression of the multiple mRNAs that are produced from the GNAS locus.
3. Investigation of the signal transduction pathways mediated by GNAS proteins. These are recently initiated studies to identify the cell signaling pathway(s) that regulate bone cell differentiation through GNAS gene products.
4. Genetics and gene regulation of FOP. Although FOP is a very rare disorder and few families showing inheritance of FOP have been identified, in recently expanded studies, we used genomic DNA samples from five families in genetic linkage analysis to identify an FOP-linked interval on chromosome 2. Mutational analysis of candidate genes identified a common mutation (R206H) in the ACVR1 gene in patients with classic features of FOP. ACVR1 encodes a BMP type I receptor. Recent studies examined the ACVR1 gene in patients with very severe or mild forms of FOP and identified additional ACVR1 mutations that suggest genotype-phenotype correlations. Loss of heterozygosity (LOH) within the candidate interval has been identified in one patient and may include a regulatory region for ACVR1; a future goal is generation of in vitro and in vivo models of the deletion.
5. BMP signaling in FOP. Even prior to the identification of the ACVR1 mutation as the cause of FOP, experimental data supported that BMP signaling is mis-regulated in FOP cells. A key finding was the over-expression and altered internalization and trafficking of the BMP type IA receptor (BMPRIA) in FOP. Continuing studies are examining the both BMP type I receptors (ACVR1 and BMPRIA). We are also conducting in vitro functional analyses of the effects of ACVR1 mutation (both the common mutation and rare mutations) on the BMP signaling pathway and on bone/cartilage cell differentiation.
6. Developmental biology of BMP signaling. Multiple tissues and organ systems require BMP signaling and ACVR1 function during development and for normal function. Our data support that the ACVR1 mutations identified in FOP are activating mutations. Although effects on bone are the main clinical consequences of ACVR1 mutation, through zebrafish and mouse models, we will investigate the effects of ACVR1 mutations on bone and cartilage as well as other tissues during vertebrate development. ACVR1 knock-in mouse models for the FOP mutation are in progress.
7. Cell lineage-tracing analyses. On-going studies are investigating the source and identity of the cells that are induced to differentiate into cartilage and/or bone in FOP and POH. We are interested in identifying the earliest cellular events that occur during the induction of bone formation.

Animal models for FOP and POH will be used to evaluate gene therapy and other strategies to treat these conditions. Translational studies and drug development will be an increasing focus within the lab.

Recent Publications

Fiori, J.L., P.C. Billings, L. Serrano de la Pena, F.S. Kaplan, and E.M. Shore. (2006). Dysregulation of the BMP-p38 MAPK signaling pathway in fibrodysplasia ossificans progressiva (FOP) patients. J. Bone Mineral Res. 21(6), 902-909.

Shore, E.M., M. Xu, G.J. Feldman, D.A. Fenstermacher, The FOP International Research Consortium, M.A. Brown, and F.S. Kaplan (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38(5), 525-527.

Billings P.C., J.L. Fiori, J.L. Bentwood, M.P. O’Connell, X. Jaio. B. Nussbaum, R.J. Caron, E.M. Shore, F.S. Kaplan (2008). Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). J. Bone Min. Res. 23 (3), 305-313.

Adegbite, N.S, M. Xu, F.S. Kaplan, E.M. Shore, R.J. Pignolo (2008). Clinical features, GNAS mutational analysis, and diagnostic criteria for progressive osseous heteroplasia (POH) and POH-like syndromes. Amer. J. Med. Genet. 146A(14): 1788-1796.

Kaplan, F.S., M. Xu, P. Seemann, M. Connor, D.L. Glaser, L. Carroll, P. Delai, E. Fastnacht-Urban, S.J. Forman, G. Gillessen-Kaesbach, J. Hoover-Fong, B. Köster, R.M. Pauli, W. Reardon, S-A. Zaidi, M. Zasloff, R. Morhart, S. Mundlos, J. Groppe, E.M. Shore. Classic and Atypical FOP Phenotypes are Caused by Mutations in the BMP Type I Receptor ACVR1. Hum. Mut. in press 2008.

Search PubMed for more articles

Lab

Rotation Projects

Rotation projects are available in most of the research areas described in the Research Summary. Specific projects will be discussed individually. Laboratory research is closely tied to clinical observation and patient care, and students are encouraged to have patient contact. (Two students completed their thesis work last year; new students are welcome.)

Lab personnel:

 

Collaborators: Frederick S. Kaplan MD, David Glaser MD, Robert J. Pignolo, MD, PhD

Post-doc/Research Associates: Salin Chakkalakal PhD; Josef Kaplan PhD; Vitali Lounev PhD; Shengliang Zhang PhD; Haitao Wang PhD

Research Specialists: Bob Caron; Ruth McCarrick-Walmsley; Alec Richardson; Meiqi Xu; Deyu Zhang