Yefu Li , MD, PhD, Assistant Professor of Developmental Biology
Dr. Li has been a faculty in the Department of Developmental Biology at Harvard School of Dental Medicine and in the Faculty of Medicine at Harvard Medical School since 1999. He has been mentoring pre-doctoral students and post-doctoral fellows in his laboratory. Research projects in Dr. Li’s laboratory have been supported by the National Institutes of Health of the United States and Non-Federal foundations.
Fields of Interest
1) HTRA1-DDR2-MMP-13 Axis in Development of Osteoarthritis
Based upon the data from our investigations and others’ studies, we propose a molecular sequence of events underlying articular cartilage degeneration as follows: Excessive mechanical stresses (either by normal mechanical loading of defective joints or overloading of normal joints) can activate signaling pathways in chondrocytes, such as transforming growth factor beta 1 and Wnt/β-catenin pathways. This, in turn, induces expression of a serine protease, high temperature requirement A1 (HTRA1). Consequences of the induction of HTRA1 are degradation of the pericellular matrix of chondrocytes and enhanced exposure of chondrocytes to type II collagen. Interaction of chondrocytes with type II collagen results in enhanced signaling through a cell membrane receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), which induces the expression of the matrix metalloproteinase 13 (MMP-13), as well as expression of DDR2 itself. MMP-13 degradation of type II collagen and aggrecan results in type II collagen and aggrecan fragments, which in turn may activate signals that further increase the synthesis of MMP-13. The result is a feedback amplification loop that causes irreversible articular cartilage degeneration. Currently, we are utilizing mouse genetic approaches to test this molecular sequence of the events in development of OA.
2) Genetic regulation of skeletogenesis
One of the interesting questions in the study of skeletogenesis is how chondrogenesis and osteogenesis are coordinated during endochondral bone development (hypertrophic cartilage replacement by bone). We have been addressing this question by utilizing a mouse mutant strain, osteochondrodystrophy (ocd). The ocd is a spontaneous mutation and homozygous, ocd/ocd, mice exhibit a short stature approximately 7 days after birth. Results from histology analysis demonstrated abnormality in growth plates of the mutant mice, such as disorganized proliferating chondrocyte columns, a reduction in numbers of proliferating chondrocytes, a small size of hypertrophic chondrocytes, a decrease in amount of trabecular bone. This suggests that ocd is a critical genetic factor regulating chondrogenesis and bone formation during the most active phase of skeletal growth. For understanding the nature of the ocd mutation, we established a high-resolution genetic linkage map of the ocd locus and obtained the physical map of the genomic interval including ocd. The interval contains about 1.1 million DNA base pairs. We found the mRNA level of one of the open-reading frames within the genomic interval was dramatically reduced, compared with that of the wild-type littermates. The cDNA and 2 kb up-stream DNA sequence of this open-reading frame was sequenced. No simple mutations, such as a point mutation, deletion and insertion, have been identified in the open-reading frame in ocd/ocd mice. We plan to continue our effort to identify the ocd mutation by direct DNA sequencing of the entire genomic interval of the ocd region.
Visiting Scholar: Dr. Tian Tang
Graduate Students: Dr. Michelle Mian
Dr. Lauren Manning
Dr. Rebecca Chen
Dr. Nithya Chickmagalur
Dr. Peter Chen