Dr. Li has been a faculty member 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 mentors pre-doctoral and post-doctoral fellows in the Li 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) A chain of the molecular events, TGF-b1 to HTRA1 to DDR2 to MMP-13 underlying articular cartilage degeneration
Based upon the data from our investigations, we propose that excessive mechanical stresses can activate TGF-b1 and Wnt/β-catenin signaling 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). Our preliminary data suggest that ocd is a critical genetic factor regulating chondrogenesis and bone formation during the most active phase of skeletal growth. We have been searching the ocd gene by positional cloning. We established a physical map of the genomic interval including ocd. The interval contains about 1.1 million DNA base pairs.
Lin Xu, MD , PhD