Thorsten Kirsch, Ph.D.
Associate Professor,
Director of Orthopaedic Research
Department of Orthopaedics
University of Maryland
School of Medicine
20 Penn Street HSFII, S003
Baltimore, MD 21201
410-706-2417
410-706-0028 fax
tkirsch@umoa.umm.edu
During endochondral ossification long bones are first cartilaginous. During this process, chondrocytes in the growth plate undergo a series of differentiation events, including proliferation, hypertrophy, terminal differentiation, mineralization and programmed cell death (apoptosis). Eventually apoptotic chondrocytes and mineralized cartilage are replaced by bone. Once the long bones have reached their final size, most of the cartilage is replaced by bone except a small rim of cartilage, called the articular cartilage. The articular cartilage plays a crucial role during normal joint function and destruction of articular cartilage is associated with osteoarthritis and rheumatoid arthritis.
My laboratory is interested in how terminal differentiation, mineralization, and apoptotic events of chondrocytes are regulated during normal development and under pathological conditions, such as osteoarthritis. We have shown that retinoic acid (vitamin A) regulates terminal differentiation, mineralization and apoptotic events in growth plate chondrocytes. Treatment of retinoic acid leads to calcium channel formation of annexins II, V and VI. Annexins are cytoplasmic proteins, which in the presence of calcium bind to acidic phospholipids. In one project, my lab is interested in the mechanisms leading to membrane binding and channel formation of annexins II, V and VI and in determining the consequences of alterations of calcium homeostasis mediated by these annexins in chondrocyte differentiation. Previous studies from our lab have demonstrated that blocking annexin channels inhibits terminal differentiation events of growth plate chondrocytes. Interestingly, these annexins bind to extracellular matrix molecules and cytoskeletal proteins. Therefore, we test the hypothesis that annexins might act mechanosensitive calcium channels controlling chondrocyte differentiation.
Annexins II, V and VI are also expressed by articular chondrocytes in osteoarthritic cartilage, but not in healthy articular cartilage. In addition, we detected other terminal differentiation markers in osteoarthritic cartilage. Therefore, we hypothesize that articular chondrocytes lose their phenotype in osteoarthritis and undergo similar differentiation events as growth plate chondrocytes, leading to terminal differentiation, mineralization and cell death. While these differentiation events are required for normal development, they lead to cartilage destruction when occurring in articular cartilage. Therefore, a focus of our research is to characterize the articular chondrocyte phenotype, factors stabilizing this phenotype and factors activating articular chondrocyte differentiation. Furthermore, we test whether annexins might be new therapeutical targets to stop or slow down the progression of osteoarthritis.
Another focus of my lab is to understand mechanisms regulating biomineralization. Physiological mineralization is important for bone development and for the proper function of bones. Mineralization, however, has to be restricted to certain sites and uncontrolled or pathological mineralization can have severe consequences. For example, mineralization of articular cartilage leads its destruction, while mineralization of cardiovascular tissues leads to morbidity and mortality. We are determining the role of Ank, a transporter, which transports intracellular pyrophosphate to the extracellular milieu, in normal and pathological mineralization of cartilage and other tissues. Mutations in the human ank gene result in hypermineralization and diseases, such as craniometaphyseal dysplasia and chondrocalcinosis. Our goal is to determine how Ank regulates extracellular pyrophosphate concentrations and subsequent mineralization.
For more information about the University of Maryland Orthopaedics Musculoskeletal Research Laboratories, please call (410) 706-2417.
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