Yefu Li, MD, PhD
Assistant Professor
Department of Developmental Biology
Telephone: 617-432-1835
Email: yefu_li@hsdm.harvard.edu

 

Our current research interests are in two areas:

1. Genetic regulation of skeletogenesis. The long-term goal of this project is to elucidate a novel genetic regulatory mechanism of skeletogenesis. For this purpose, we study a spontaneous mouse mutation, osteochondrodystrophy (Ocd). Ocd is an autosomal recessive disorder associated with cartilage and bone defects. Preliminary data from our laboratory demonstrate that the mutation in Ocd results in decreased chondrocyte proliferation and bone formation during skeletal growth.  On the basis of high-resolution genetic linkage and physical maps of the Ocd locus, we have positioned Ocd in a defined chromosome region (about 1 million base-pairs containing 37 known genes and open reading frames). To identify the Ocd gene, these genes are being examined by direct DNA sequence analysis.
   
   
2. Role of a collagen receptor, discoidin domain receptor 2, in pathogenesis of osteoarthritis (OA). The study is aimed at understanding pathogenetic mechanisms of OA by using two mutant mouse strains, type XI collagen-haploinsufficienct (chondrodysplasia, cho/+) and type IX collagen-deficient (Col9a1-/-) mice. Our previous study demonstrated that cho/+ and Col9a1-/- mice revealed characteristic phenotype of OA-like changes in their knee and temporomandibular joints. Interestingly, we found that the expression of discoidin domain receptor 2 (Ddr2) was increased in knee articular cartilages of both mutant mouse strains, associated with the increased expression of a matrix-degrading enzyme, Mmp-13 (matrix metalloproteinase 13). More importantly, results from our study indicated that the expression of Ddr2 and Mmp-13 was increased in the articular cartilage of knee joints of mice surgically induced OA and in human hip OA cartilages. We also found that activation of Ddr2 resulted in the increased expression of Mmp-13 in mouse and human chondrocytes. On the basis of our findings, we hypothesize that DDR2 may play a significant role in the progression of genetic forms of OA, as well as non-genetic forms of OA.
   
   
   Selected Publications:

   1.  Li, Y., Seegmiller, R.E., Castagnola, P., and Olsen, B.R. (1989) Evidence for type IX collagen in fetal cartilage of mice with chondrodysplasia. Teratology  39:465.
   

   2.  Li, Y., Booth, G.M., and Seegmiller, R.E. (1989) Evidence for embryotoxicity of gossypol in mice and chicks with no evidence of mutagenic activity in the Ames test. Reprod. Toxicol.1:59-62.
   

   3.  Li, Y., Lacerda, D.L., Warman, M.L., Beier, D.R., Oxford, J.T., Morris, N.P., Andrikopoulos, K., Ramirez, F., Wardell, B.B., Lifferth, G.D., Teuscher, C., Woodward, S.R., Taylor, B.A., Seegmiller, R.E., and Olsen, B.R. (1995) A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis.  Cell 80:423-430.
   

   4. Böhme, K., Li, Y., Oh, S.P., Olsen, B.R. (1995) Primary structure of the long and short splice variants of mouse collagen XII and their tissue-specific expression during embryonic development. Devel. Dyn.  204:432-445.
   

   5. Haimes, H., Jimenez. P., Li, Y., Shinya, T., and Olsen, B. (1995) Overexpression of the NC4 domain of type IX collagen induces osteoarthritis in mice. Inflam. Res. 44:S127-S128.
   

   6. Pace, J., Li, Y., Seegmiller, R., Teuscher, C., Taylor, B., and Olsen, B.R. (1997) Disproportionate micromelia (Dmm) in mice caused by a mutation in the C-propeptide coding region of Col2a1 . Devel. Dyn.  208:25-33.
   

   7. Li, Y. and Olsen, B. Murine models of human osteochondrodysplasias. (1997) Matrix Biol. 16:49-52.
   

   8. Fulop, C., Kamath R., Li, Y., Otto, J., Salustri, A., Olsen, B., Glant, T., and Hascall, C. (1997) Coding sequence, exon-intron structure and chromosomal localization of murine TNF-stimulated gene 6  that is specifically expressed by expanding cumulus cell-oocyte complexes. Gene. 202:95-102.
   

   9. Otto, J. M., Cs-Szabo, G., Gallagher, J., Velins, S., Milecz, K., Buzas, E., Li, Y., Olsen, B.R. and Glant, T.T. (1999) Identification of four non-MHC loci linked to profeoglycan-induced arthritis in mice. Arthritis. Rhem 42:2524-2531.
   

   10.  Kipnes J.R, Xu, L, Han, F, Rallapalli, R, Jimenez, S, Hall, D.J, Tuan, R.S, and Li, Y. (2000) Molecular cloning and expression patterns of mouse cartilage oligomeric matrix protein gene.   Osteoarth. & Cartil. 8:236-239.
   

   11. Xu, L., Tan, L, Goldring, M.B., Olsen, B.R. and Li, Y. (2001) Expression of frizzled genes in mouse costochondroal chondrocytes. Matrix Biol. 20:147-151.
   

   12.  Han, F., Kipnes, J.R., Li, Y., Tuan, R.S. and Hall. D.J. (2002) The murine COMP (cartilage oligomeric matrix protein) promoter contains a potent transcriptional repressor region. Osteoarth Cartil. 10:638-645.
   

   13.  Xu, L, Flahiff, C.M, Waldman, B.A, Wu, D., Olsen, B.R, Setton, L. A. and Li, Y. (2003) Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of chondrodysplasia (cho) mice. Arthritis Rheum. 48:2509-2518
   

   14.  Czipri, M, Otto, J.M, Cs-Szabo, G, Kamath, R.V, Vermes, C, Firneisz, G, Kolman, K.J, Watanabe, H, Li, Y, Roughley, P.J, Yamada, Y, Olsen, B.R. and Glant, T.T. (2003) Genetic rescue of chondrodysplasia and the perinatal lethal effect of cartilage link protein-deficiency. J Biol Chem. 278: 39214-39223
   

   15.  Lu, Y, Guo, C, Liu, Q, Zhang, X, Cheng, L, Li, J, Chen, B, Gao, G, Zhou, H, Guo, Y, Li, Y, Gong, Y. (2003) A novel mutation of keratin 9 in epidermolytic palmoplantar keratoderma combined with knuckle pads. American Journal of Medical Genetics 3: 345-349.
   

   16.  Flahiff, C.M, Comrie, B, Li, Y, Olsen, B.R. and Setton, L.A. (2004) Aging contributes to altered cartilage mechanics in a type XI collagen gene mutation model of osteoarthritis.  Trans. Orthop. Res. Soc. 29:535.
   

   17.  Li, Y, Xu, L, Hasturk, H, DePalma, S.R. and Van Dyke, T. E. (2004) Localized        aggressive periodontitis is linked to human chromosome 1q25. Hum. Genet. 114: 291-297.
   

   18.  Xu, L, Peng, H, Wu, D, Hu, K, Goldring^, M.B, Olsen, and Li, Y. (2005) Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in cho/+ mice. J. Biol.Chem. 280:548-555.
   

   19.    Hu, K, Xu, L,Cao, L, Flahiff, C.M, Setton, L.A, Youn, I, Brussiau, J, Ho, K, Guilak, F, Olsen, BR, and Li, Y. Pathogenesis of Osteoarthritis-like Changes in Joints of Type IX Collagen-Deficient Mice. Arthritis. Rheum. (in press)