ABOUT OUR LAB
The research program of the Fitzgerald laboratory is focused on genetic and degenerative diseases of the musculoskeletal system with an emphasis on extracellular matrix macromolecules. From a clinical perspective, knowledge from these studies will aid in devising new diagnostic tools and strategies to improve musculoskeletal tissue repair and regeneration.
Collagen VI and musculoskeletal pathology - A major part of the Fitzgerald lab research program is focused on three new collagen VI genes recently identified in the laboratory; COL6A4, COL6A5 and COL6A6. The discovery of these new genes doubles the collagen VI family from three to six members and raises a host of new, clinically-relevant issues regarding the role of collagen VI structure in disease. The overall goal of the research program is to define the function of these new chains. To achieve this, research efforts are focused on three areas:
1) The identification and characterization of COL6A5 and COL6A6 mutations in musculoskeletal genetic disease. These experiments will expand the spectrum of collagen VI variation in human disease.
2) The in vivo analysis of collagen VI function using transgenic and knock-out mouse strategies. These investigations will assess the effect of the absence of individual collagen VI chains on musculoskeletal development.
3) The mechanism of collagen VI trimerization and higher-order assembly. These biochemical studies will help us to define how these new chains assemble into collagen VI molecules.
Articular cartilage and osteoarthritis - One of the major clinical problems for Orthopaedic practitioners is the repair of full thickness articular cartilage defects because there are no effective treatments that repair the defect with the same structural and functional properties as the original cartilage. The MRL/MpJ strain of mice has recently been shown to 'regenerate' through-and-through ear hole punch wounds. We asked whether articular cartilage lesions regenerated in MRL mice. An articular cartilage lesion that penetrated the subchondral bone was replaced with hyaline-like cartilage in MRL mice. The new cartilage was positive for markers of articular cartilage including proteoglycan, collagen II and collagen VI suggesting that MRL mice possesses an intrinsic ability to 'regenerate' full-thickness articular cartilage defects. This is a novel and exciting finding that will be followed up in ongoing studies that seek to address the mechanism of regeneration. The knowledge gained from these studies will be used to develop new treatments for knee cartilage lesions in humans.
A second investigates whether reduced biomechanical forces on the joint leads to osteoarthritis. Human and animal studies demonstrate that cartilage breakdown can result from abnormal (both increased and decreased) mechanical forces on cartilage. We suggest that the absence of significant biomechanical forces experienced during periods of microgravity affects that ability of the chondrocyte to maintain healthy functioning cartilage leading to accelerated cartilage breakdown and osteoarthritis. This could be a major consequence of long-term spaceflight. As part of a NASA-funded project we are investigating whether cartilage breakdown occurs following exposure to microgravity. The goal of the project is to conduct cell and molecular analyses on articular cartilage of mice exposed to microgravity for an extended period of time for evidence of cartilage degradation. These studies will help us understand whether osteoarthritis is likely to result during long-term spaceflight and to elucidate the underlying basis of osteoarthritis and lead to new biomarkers and treatment strategies for this debilitating disease.
Fitzgerald, J., Lamandé, S. L. and Bateman, J. F. (1999) Proteasomal degradation of unassembled mutant proa1(I) collagen chains. J. Biol. Chem. 274 (39): 27392.
Fitzgerald, J., Mörgelin, M., Selan, C., Wiberg, C., Keene, D. R., Lamandé, S. R and Bateman, J. F. (2001) The amino-terminal N5 subdomain of the a3(VI) chain is important for collagen VI microfibril formation. J Biol. Chem. 276 (1): 187.
Fitzgerald, J. and Bateman, J.F. (2004) Why mice have lost genes for COL21A1, STK17A, GPR145 and AHRI: evidence for gene deletion at evolutionary breakpoints in the rodent lineage. Trends in Genetics 20: 408
Allen, J., Bateman J. F., Hansen, U., Wilson, R., Bruckner, P., Owens, R.T., Sasaki, T., Timpl, R. and Fitzgerald, J. (2006) WARP is a novel multimeric component of the chondrocyte pericellular matrix that interacts with perlecan. J. Biol. Chem. 281 (11): 7341.
Fitzgerald, J., Rich, C, Burkhardt, D., Allen, J. Herzka, A. and Little, C. B. (2008) Evidence for articular regeneration in MRL/MpJ mice. Osteoarthritis and Cartilage. 16(11):1319.
Fitzgerald J, Rich C, Zhou FH, Hansen U. (2008) Three novel collagen VI chains, alpha 4(VI), alpha 5(VI) and alpha 6(VI). J Biol Chem. 283(29):20170.
Allen JM, Zamurs L, Brachvogel B, Schlötzer-Schrehardt U, Hansen U, Lamandé SR, Rowley L, Fitzgerald J, Bateman JF (2009) Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function. J Biol Chem. 284(18):12020.
National Institutes of Health, NASA, Muscular Dystrophy Association, Medical Research Fund of Oregon, National Football League Charities, OHSU Gerlinger Award.