Audrey McAlinden, Ph.D.

Associate Professor
Orthopaedic Surgery
Cell Biology and Physiology

Developmental, Regenerative and Stem Cell Biology Program

  • 314-454-8860

  • 314-454-7800

  • 314-454-8860

  • 314-454-5900

  • 8233

  • BJC Institute of Health, 11th Floor, 660 South Euclid Avenue.

  • mcalindena@wudosis.wustl.edu

  • http://audreymcalinden.org

  • microRNAs; stem cells; skeletal development and regeneration; cartilage; chondrocyte differentiation; pre-mRNA alternative splicing

  • Molecular mechanisms regulating skeletal development

Research Abstract:

My research program focuses on understanding mechanisms regulating skeletal development with an emphasis on cartilage tissue. Projects are underway to study: 1) the role of non-coding microRNAs in regulating chondrocyte differentiation and homeostasis; 2) the biological significance of type II procollagen pre-mRNA alternative splicing in post-natal cartilage and endochondral bone development.

1) The role of non-coding microRNAs in regulating chondrocyte differentiation and homeostasis:

Small, non-coding microRNAs (miRNAs) are known to play important roles in tissue development and disease. Currently, very little is known about the expression of miRNAs in human skeletal tissue. We have carried out state-of-the-art laser capture microdissection and OpenArray analysis to determine differentially-expressed microRNAs in different regions of human embryonic limb cartilage containing chondrocytes at distinct stages of differentiation. This is the first study of its kind and we have identified a number of candidate microRNAs to pursue further to determine functional roles in regulating stem cells differentiation toward the chondrocyte lineage. We are also utilizing cartilage joint loading murine models to elucidate the role of specific miRNAs in regulating cartilage tissue homeostasis. The long-term goals of this work are to develop miR-based strategies to regenerate cartilage tissue as well as to prevent/ameliorate cartilage breakdown caused by joint trauma or osteoarthritis, for example.

2) The biological significance of type II procollagen (Col2a1) pre-mRNA alternative splicing in post-natal cartilage and endochondral bone development:

One of the most important alternative splicing events during cartilage development involves the type II collagen gene (Col2a1). Type II collagen is the major extracellular matrix protein in cartilage tissue and alternative splicing of Col2a1 pre-mRNA results in production of an “embryonic” isoform (type IIA) and a “mature” isoform (type IIB) by the inclusion or exclusion of exon 2, respectively. We have since discovered two more splice forms (type IIC and IID). We hypothesize that IIC is functional only at the RNA level to regulate production of the other translated isoforms. Type IID differs from IIA by one amino acid but they may carry out distinct biological functions in vivo. We have generated two mouse models where Col2a1 exon 2 alternative splicing has been inhibited. One model exclusively expresses the embryonic IIA isoform even during post-natal development: the ultrastructure of the collagen network in the cartilage of these mice is abnormal and a bone phenotype has been identified. We are currently characterizing the second mouse model where the IIC splicing event has been inhibited. These mouse models are important biological tools to investigate the importance of collagen matrix assembly in generating proper cartilage and bone tissue with optimal biomechanical properties.

Selected Publications:

1. McAlinden, A., Varghese, N., Wirthlin, L., Chang, LW. Differential expression of microRNAs between distinct regions of developing human cartilage. PLoS One Sep 9; 8(9): e75012, 2013.

2. McAlinden, A., Traeger, G., Hansen, U., Weiss, M.A., Ravindran, S., Wirthlin, L., Eyre, DR., Fernandes, RJ. Molecular properties and fibril ultrastructure of types II and XI collagens in cartilage of mice expressing exclusively the 1(IIA) collagen isoform. (Matrix Biology – In Press).

3. Rai, M.F., Schmidt, E.J., McAlinden, A., Cheverud, J.M., Sandell, L.J. Molecular Insight into the Association between Cartilage Regeneration and Ear Wound Healing in Genetic Mouse Models: Targeting New Genes in Regeneration. G3: Genes, Genomes, Genetics (Bethesda), Sep 3, PMID: 24002865, 2013.

4. McAlinden, A., Shim, K-H., Wirthlin, L., Ravindran, S., Hering TM Quantification of Type II Procollagen Splice Forms Using Alternative Transcript-qPCR (AT-qPCR). Matrix Biology Sep 31(7-8):412-20, 2012.

5. Bonar, S., Brydges, S.D., Mueller, J.L., McGeough, M.D., Pena, C., Chen, D. Grimston, S.K., Hickman-Brecks, C.L., Ravindran, S., McAlinden, A., Novack, D.V., Kastner, D.L., Civitelli, R., Hoffman, H.M., Mbalaviele, G. Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice PLoS ONE 7(4):e35979, 2012. Epub 2012 Apr 27.

6. Lewis, R., Ravindran, S., Wirthlin, L., Traeger, G., Fernandes, R.J., McAlinden, A. Disruption of the Developmentally-Regulated Col2a1 Pre-mRNA Alternative Splicing Switch in a Transgenic Knock-in Mouse Model. Matrix Biology. Apr:31(3):214-26, 2012.

7. Ravindran, S., Roam, J., Hering, TM., Elbert, DL., McAlinden, A. Changes of Chondrocyte Expression Profiles in Human MSC Aggregates in the Presence of PEG microspheres and TGF-3. Biomaterials. Nov;32(33):8436-45, 2011.

8. Ravindran, S., Boyer, MI., Martens, E., Ntouvali, H., McAlinden, A. Assessment of Epiphyseal Plate Allograft Viability and Function Following Ex Vivo Storage in University of Wisconsin Solution. Journal of Pediatric Orthopaedics Oct-Nov; 31(7):803-810, 2011.

9. Rich, JT., Rosova, I., Nolta, JA., Myckatyn, TM., Sandell, LJ and McAlinden, A. Transcriptional Profiling Reveals Upregulation of Runx2 and Osterix During TGF-β3 induced in vitro Chondrogenesis of Human Adipose-derived Stromal Cells. Biochemical and Biophysical Research Communications 372(1): 230-235, 2008.

10. McAlinden, A., Johnstone B., Kollar, J., Yoo, J., Kazmi, N., and Hering, TM. Expression of two novel alternatively spliced COL2A1 isoforms during chondrocyte differentiation. Matrix Biology 27(3): 254-66, 2008.

Last Updated: 10/11/2013 1:42:45 PM

Expression of the embryonic isoform of type II procollagen (IIA; green) in 1 month old knee joint cartilage. Immunostained tissue is from a transgenic mouse engineered to persistently express type II collagen embryonic isoforms post-natally.
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