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Tamara Alliston Ph.D.

Skeletal Cell Differentiation and Matrix Quality

Tamara Alliston Ph.D.

One in three American adults suffers from arthritis symptoms, yet the molecular basis of this degenerative skeletal disease remains unclear. Our research focuses on the molecular pathways controlling mesenchymal stem cell differentiation, how these pathways function in normal skeletal tissue, and how they can be harnessed to repair tissue damaged in degenerative skeletal disease. To answer these questions, we combine molecular, cellular, physiological, and materials science approaches. I believe this interdisciplinary strategy will lead to the identification of targets to prevent skeletal disease or to improve skeletal repair.

A current focus is to understand the mechanisms by which TGF-beta regulates osteoblast and chondrocyte differentiation. Cell-based studies are used to identify signaling pathways and transcription factors downstream of TGF-beta. In vivo studies allow examination of the role of these pathways in bone and cartilage. A key goal of this work is to understand the control of skeletal matrix formation and quality.

Current Research Goals:

1. Understand the mechanisms by which TGF- b regulates osteoblast and chondrocyte differentiation TGF- b is a key regulator of osteoblast and chondrocyte differentiation. Abnormal TGF- b signaling has been implicated in a number of human skeletal diseases. Likewise, mouse models with alterations in TGF- b signaling exhibit a variety of skeletal defects, including osteoarthritis and osteoporosis. Cell-based studies are used to identify signaling pathways and transcriptional regulators downstream of TGF- b in the control of cell differentiation. In vivo studies allow examination of the role of these pathways in bone and cartilage.

2. Understand the regulation of bone matrix material properties With the promise of harnessing stem cells to generate skeletal tissue, remains the challenge of creating tissue of sufficient mechanical quality. Bone matrix material properties, in addition to bone mass and architecture, determine the ability of bone to resist fracture. However, very little is known about the mechanisms that control the material properties of skeletal matrices. We have recently identified TGF- b as a key regulator of bone matrix mechanical properties and composition. We now aim to identify the pathways by which TGF- b controls these properties. One goal is to identify therapeutic agents that may improve the material properties of skeletal matrices, and consequently, improve or protect skeletal function.

3. Understand the role of bone matrix quality in bone disease-associated hearing loss The composition and mechanical properties of bone are critically important for normal hearing. This is made evident by the hearing loss associated with several bone diseases. We are testing the hypothesis that hearing loss in these bone diseases results from defective matrix material properties of ear bones. These studies will provide insight into the role of bone matrix in auditory structure and function.

Selected publications:

Balooch G, Balooch M, Nalla RK, Schilling S, Filvaroff EH, Ritchie RO, Marshall GW, Marshall SJ, Derynck R, and Alliston T . (2005) TGF- b signaling regulates the mechanical properties and composition of bone matrix. P.N.A.S. 102:18813-8.

Kang J.S., Alliston T , Delston R, and Derynck R. (2005) Repression of Runx2 function by TGF- b through recruitment of class II histone deacetylases by Smad3. EMBO J. 24:2543-55.

Alliston T , Ko TC, Cao Y, Liang Y-Y, Feng X-F, Chang C, and Derynck R. (2005) Repression of activin and BMP-inducible transcription by Evi-1. J Biol Chem. 280:24227-37. Selvamurugan N, Kwok S, Alliston T , Reiss M, Partridge NC. (2004) Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by a cross-talk between smad and MAPK signaling pathways and their components, Smad2 and runx2. J Biol Chem . 279:19327-34.

Alliston T , Derynck R. (2002) Interfering with bone remodelling. Nature. 416:686-7.

Alliston T , Choy L, Ducy P, Karsenty G, Derynck R. (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 20:2254-2272.

Alliston T , and Derynck R. (2000) TGF-beta in Skeletal Development and Maintenance. In Canalis, E, (ed.), Skeletal Growth Factors . Lippincott, Williams & Wilkins, Philadelphia , PA , pp 233 - 247.