Professor, Department of Orthopaedic Surgery
Professor, Department of Cell Biology
The primary focus in my laboratory is to understand the mechanisms regulating the differentiation events of precursor cells into mature skeletal tissue cells. We specifically focus on the role of two proteins, annexins and progressive ankylosis gene (Ank) in these differentiation events. Annexins are Ca2+ channel forming proteins, which also interact with extracellular matrix proteins. Our work has shown that annexins mediate Ca2+ influx into growth plate chondrocytes thereby stimulating terminal differentiation and mineralization events in these cells. In addition, interaction of annexin V with types II and X collagen stimulates its Ca2+ channel activities and these interactions further accelerate terminal differentiation events. Our laboratory was the first to show that articular chondrocytes in osteoarthritis undergo similar terminal differentiation events as growth plate chondrocytes. In addition, annexins are expressed by osteoarthritic chondrocytes but not by healthy articular chondrocytes, suggesting that annexins may also control terminal differentiation events in osteoarthritis leading to cartilage destruction. Therefore, annexins may provide novel therapeutic targets to slow down or prevent the progression of osteoarthritis. In a second project we investigate the role of Ank in skeletal tissue cell differentiation. Ank is highly expressed by hypertrophic growth plate chondrocytes and the protein transports intracellular pyrophosphate to the extracellular milieu. In the presence of alkaline phosphatase pyrophosphate is being cleaved into phosphate, and phosphate then acts as a signaling molecule that regulates cell differentiation events. Our findings suggest that Ank regulates terminal differentiation and mineralization events of growth plate chondrocytes by altering pyrophosphate/phosphate homeostasis. In addition, mice lacking a functional Ank protein have a severely reduced bone mass. Our findings further suggest that Ank is required for the differentiation of osteoblasts and osteoclasts and that the lack of Ank prevents or slows down the differentiation of precursor cells into osteoblasts and osteoclasts.
Dr. Kirsch's research interests include chondrocyte and osteoblast biology and differentiation, molecular mechanisms regulating physiological and pathological mineralization, and osteoarthritis. His research has been funded by several sources, including the National Institutes of Health and the Arthritis Foundation. He has published more than 50 articles in peer-reviewed journals and spoken at numerous national an international meetings.
Vice Chair for Research, Department of Orthopaedic Surgery
PhD from Friedrich Alexander University Erlangen
University of Pennsylvania, Dr. Pacifici
Osteoarthritis & cartilage. 2021 Nov 11;
Aging cell. 2021 Jul 09; e13427
International journal of molecular sciences. 2021 Jun 30; 22(13):
Journal of orthopaedic research. 2020 Apr; 38(4):731-739
Scientific reports. 2020 Jan 29; 10:1441
Inflammation. 2019 Oct; 42(5):1808-1820
American journal of sports medicine. 2019 Feb 20; 363546519825498
Biomacromolecules. 2018 05 14; 19(5):1614-1624