Catherine B. Kirn-Safran, Ph.D.

Teaching

Introductory Biology II

(BISC208013, BISC208014)

Research Interests

Dr. Kirn-Safran is best known for her work on the study of the terminal differentiation of progenitor cells into cells producing an organized mineralized extracellular matrix (ECM) during murine embryonic development. This area of research includes the study of the mechanisms of cartilage (chondrogenesis), bone (osteogenesis), and tooth (odontogenesis) development.

During the past years, Dr. Kirn-Safran has worked to develop a knock-out mouse model that disrupts the expression of a ribosomal protein of the ribosome large subunit, RPL29, which is abundant in developing bone. The phenotypic characterization of these mutant mice showed global growth deficiencies evident both prior to and after birth (Kirn-Safran et al., 2007). Interestingly, low birth weight was accompanied by a short stature phenotype. Reduced rates in proliferation and protein synthesis are believed to be the cause of this phenotype. Dr. Kirn-Safran's ongoing research focuses on establishing how altered ECM protein production/secretion influences bone properties in the RPL29-deficient mouse model. She is currently collaborating with Dr. Liyun Wang (UD, Department of Mechanical Engineering), who is a specialist in bone mechanics and studies genetic influences on cellular mechanotransduction in bone. In addition, other genetic mouse models developing chondral defects are studied to understand the molecular mechanisms regulating joint dysplasia syndromes.

Recently, Dr. Kirn-Safran's group has been working on identifying novel strategies to slow osteoarthritis progression. One approach consists of using heparan sulfate-bearing biomaterials coupled to hyaluronan microgels for prolonged delivery of chondrogenic factors. This work is conducted in collaboration with Dr. Xinqiao Jia (UD, Department of Materials Science and Engineering). The therapeutic potential of these complexes is tested in vitro on cartilage stem cell cultures and in a mouse model of early osteoarthritis using an intra-articular injection approach. Discovery of novel methods for activating stem cells in damaged cartilage will benefit a wide range of patients affected with chondral lesions.

Current Projects

• NIH COBRE, Perlecan, Heparanase, and HIP/RPL29 in Cartilage Growth and Healing.
• DRI Pilot, T-Type Calcium Channel: A novel target for treatment of osteoarthritis

Research Group

Padma P. Srinivasan, M.B. B.S. - Graduate Student (M.B. B.S., Mahatma Gandhi Medical College & Research Institute, India). Use of experimental and genetic mouse model of osteoarthritis to study the molecular mechanisms involved in disease progression.

Kristen M. Roach - Research Assistant. Mouse models of osteoarthritis

Selected Publications

• Jones DT, Lechertier T, Reynolds LE, Mitter R, Robinson SD, Kirn-Safran CB, Hodivala-Dilke KM. Endogenous ribosomal protein L29 (RPL29): a newly identified regulator of angiogenesis in mice. Dis Model Mech. 2013;6(1):115-24.
• Srinivasan PP, McCoy SY, Jha AK, Yang W, Jia X, Farach-Carson MC, Kirn-Safran CB. Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis. Biomed Mater. 2012;7(2):024109.
•  Keel S, Phelps S, Sabo K, O'Leary MN, Kirn-Safran CB, Abkowitz JL.Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis. Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis.Exp Hematol. 2012;40(4):290-4.
•  McCoy SY, Falgowski KA, Srinivasan PP, Thompson WR, Selva EM, Kirn-Safran CB.  Serum xylosyltransferase 1 level increases during early posttraumatic osteoarthritis in mice with high bone forming potential. Bone (Special Issue on Osteoarthritis) 2011 Dec 2. [Epub ahead of print]
• Thompson WR, Modla S, Grindel BJ, Czymmek KJ, Kirn-Safran CB, Wang L, Duncan RL, Farach-Carson MC. Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res. 2011; 26(3):618-29.
• Sloofman LG, Verdelis K, Spevak L, Zayzafoon M, Yamauchi M, Opdenaker LM, Farach-Carson MC, Boskey AL, Kirn-Safran CB. Effect of HIP/ribosomal protein L29 deficiency on mineral properties of murine bones and teeth. Bone. 2010;47(1):93-101.
• Jha AK, Yang W, Kirn-Safran CB, Farach-Carson MC, Jia X. Perlecan domain I-conjugated, hyaluronic acid-based hydrogel particles for enhanced chondrogenic differentiation via BMP-2 release. Biomaterials. 2009 Dec;30(36):6964-75.
• Kirn-Safran C, Farach-Carson MC, Carson DD. Multifunctionality of extracellular and cell surface heparan sulfate proteoglycans. Cell Mol Life Sci. 2009;66(21): 3421- 3434.
• Oristian DS, Sloofman LG, Zhou X, Wang L, Farach-Carson MC, Kirn-Safran CB. Ribosomal protein L29/HIP deficiency delays osteogenesis and increases fragility of adult bone in mice. J Orthop Res. 2009;27(1):28–35.
• Brown AJ, Alicknavitch M, D'Souza SS, et al. Heparanase expression and activity influences chondrogenic and osteogenic processes during endochondral bone formation. Bone. 2008;43(4):689–699.
• Kirn-Safran CB, D'Souza SS, Carson DD. Heparan sulfate proteoglycans and their binding proteins in embryo implantation and placentation. Semin Cell Dev Biol. 2008;19(2):187–193.
• Kirn-Safran CB, Oristian DS, Focht RJ, Parker SG, Vivian JL, Carson DD. Global growth deficiencies in mice lacking the ribosomal protein HIP/RPL29. Dev Dyn. 2007;236(2):447–460.
• Kirn-Safran CB, Gomes RR, Brown AJ, Carson DD. Heparan sulfate proteoglycans: coordinators of multiple signaling pathways during chondrogenesis. Birth Defects Res C Embryo Today. 2004;72(1):69–88.
• Miller SA, Brown AJ, Farach-Carson MC, Kirn-Safran CB. HIP/RPL29 down-regulation accompanies terminal chondrocyte differentiation. Differentiation. 2003;71(6):322–336.
• Kirn-Safran CB, Julian J, Fongemie JE, Hoke DE, Czymmek KJC, Carson DD. Changes in the cytologic distribution of heparin/heparan sulfate interacting protein/ribosomal protein L29 (HIP/RPL29) during in vivo and in vitro mouse mammary epithelial cell expression and differentiation. Dev Dyn. 2002;223(1):70–84.
• Kirn-Safran CB, Dayal S, Martin-DeLeon PA, Carson DD. Cloning, expression, and chromosome mapping of the murine Hip/Rpl29 gene. Genomics. 2000;68(2):210–219.
• Kirn-Safran CB, Carson DD. Dynamics of uterine glycoconjugate expression and function. Semin Reprod Endocrinol. 1999;17(3):217–227.
• Begue-Kirn C, Krebsbach PH, Bartlett JD, Butler WT. Dentin sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin: tooth-specific molecules that are distinctively expressed during murine dental differentiation. Eur J Oral Sci. 1998;106(5):963–970.
• Begue-Kirn C, Ruch JV, Ridall AL, Butler WT. Comparative analysis of mouse DSP and DPP expression in odontoblasts, preameloblasts, and experimentally induced odontoblast-like cells. Eur J Oral Sci. 1998;106 Suppl 1:254–259.
• Heikinheimo K, Begue-Kirn C, Ritvos O, Tuuri T, Ruch JV. Activin and bone morphogenetic protein (BMP) signalling during tooth development. Eur J Oral Sci. 1998;106 Suppl 1:167–173.
• Hoke DE, Regisford EG, Julian J, Amin A, Begue-Kirn C, Carson DD. Murine HIP/L29 is a heparin-binding protein with a restricted pattern of expression in adult tissues. J Biol Chem. 1998;273(39):25148–25157.
• Sun ZL, Fang DN, Wu XY, et al. Expression of dentin sialoprotein (DSP) and other molecular determinants by a new cell line from dental papillae, MDPC-23. Connect Tissue Res. 1998;37(3-4):251–261.
• Heikinheimo K, Begue-Kirn C, Ritvos O, Tuuri T, Ruch JV. The activin-binding protein follistatin is expressed in developing murine molar and induces odontoblast-like cell differentiation in vitro. J Dent Res. 1997;76(10):1625–1636.
• Smith AJ, Cassidy N, Perry H, Begue-Kirn C, Ruch JV, Lesot H. Reactionary dentinogenesis. Int J Dev Biol. 1995;39(1):273–280.
• Smith AJ, Tobias RS, Cassidy N, Begue-Kirn C, Ruch JV, Lesot H. Influence of substrate nature and immobilization of implanted dentin matrix components during induction of reparative dentinogenesis. Connect Tissue Res. 1995;32(1-4):291–296.
• Begue-Kirn C, Smith AJ, Loriot M, Kupferle C, Ruch JV, Lesot H. Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation. Int J Dev Biol. 1994;38(3):405–420.
• Lesot H, Begue-Kirn C, Kubler MD, et al. Experimental Induction Of Odontoblast Differentiation And Stimulation During Reparative Processes. Cells Mat. 1993;3(2):201–217.
• Begue-Kirn C, Smith AJ, Ruch JV, et al. Effects of dentin proteins, transforming growth factor beta 1 (TGF beta 1) and bone morphogenetic protein 2 (BMP2) on the differentiation of odontoblast in vitro. Int J Dev Biol. 1992;36(4):491–503.