The Abramson Lab

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Abramson Lab

Logos for NYU School of Medicine, Department of Medicine, and Division of Rheumatology

Cartilage Biology

Illustrations of healthy and diseased joints.

Osteoarthritis is one of the most common musculoskeletal diseases affecting millions of patients. It is a painful disabling disease that is charactized clinically by joint stiffness and dysfunction. OA has been considered a disease of articular cartilage. Due to advancement in imaging and molecular cell biology it is increasingly appreciated that OA involves the entire joint including the subchondral bone, menisci, ligaments, capsule and synovium (Figure 1).
Although both bone and synovium have important roles in the pathogenesis of OA, most interest in disease modifying treatments has focused on molecular events within articular cartilage. Among these tissues, articular cartilage is an avascular, alymphatic and fibrous connective tissue, which acts as cushion between joints thus preventing bones from rubbing against each other. Articular cartilage is maintained by resident chondrocytes and orchestrates a balance between matrix synthesis and breakdown thus facilitating normal tissue homeostasis. In OA this balance is disrupted and the processes that drive cartilage breakdown predominate, ultimately leading to joint degeneration (Figure 2).
Illustration of cartilage destruction.

In OA the cartilage cells – chondrocytes – undergo a series of complex changes, that are thought to drive the disease process; these include cellular hypertrophy, increased proliferation, catabolic activation and ultimately, cell death. The regulation of these pathological changes at different stages of disease is under intensive study, with focus on the biomechanical and biochemical signals that regulate each of these discrete chondrocyte responses.

Illustration of gene expression profiling. In an effort to identify the underlying cellular changes that are responsible for OA development, we have studied global changes in gene expression in normal and arthritic tissues using microarray and bioinformatics tools. Using this technology we have identified genes and gene families that are either switched on or shut off in osteoarthritis (Figure 3).
This work has led to the identification of a number of proteins including cytokines, growth factors and extracellular matrix proteins and regulatory RNA molecules (micro RNAs) that are important for chondrocyte function. Using animal and in vitro cell and tissue culture models we are investigating their role in chondrocyte (cartilage) homeostasis, development and disease.

Projects:

1. F-spondin: From our microarray gene profiling studies, we identified a novel extra cellular matrix protein, F-spondin, in arthritic cartilage. We found that F-spondin, a member of the thrombospondin family of proteins, is significantly increased in osteoarthritic cartilage as well as in rodent models of OA (Figure 4). Further studies from our laboratory indicate that F-spondin has significant effects on human chondrocyte metabolism and skeletal development where it acts to regulate mineralization of cartilage during and long bone formation (endochondral ossification). Ongoing projects are investigating the effects of F-spondin gene knockout on bone and cartilage development, and progression of osteoarthritis in a surgically induced rodent model. We are also investigating the mechanism of F-spondin mediated activation of TGF-b – a pleiotropic growth factor that regulates inflammation and wound repair in a variety of connective tissues. Understanding the regulation of chondrocyte functions by F-spondin could lead to novel strategies for cartilage repair and disease modifying treatments for osteoarthritis.

F-spondin
2. Inflammatory Mediators: Understanding the role of inflammatory mediators in the pathogenesis of cartilage degeneration in osteoarthritis (OA) is increasingly recognized as a strategy for the development of mechanism-based therapeutics aimed to slow disease progression. While the catabolic effects of interleukin-1beta, tumor necrosis factor-alpha and nitric oxide are well described, the consequences of the excess production of eicosanoids, (are family of lipids) in the progressive osteoarthritis, are poorly understood. This lack of clarity is, in part, because diverse eicosanoid end-products (Figure 5), are poorly characterized in OA, act via distinct surface receptors, intracellular signaling pathways, and transcription factors to exert highly dissimilar effects on cellular functions. We performed comprehensive determination of the predominant eicosanoids produced by OA chondrocytes in order to clarify the effects of specific end-products on selected gene expression and cartilage homeostasis. Using enzyme immunoassay and LC/MS-MS, we characterized the profile and enzymatic source of the eicosanoids produced by OA cartilage. Based upon our preliminary Studies, we focused on the regulation and action of PGE2. Following the identification of OA predominant eicosanoids, we assessed their effects on differential gene expression of OA and normal chondrocytes. Currently, we are determining the effects of PGE2 and other OA predominant eicosanoids on chondrocyte metabolism (proteoglycan synthesis and degradation), inflammatory mediator production and apoptosis. These studies will provide new insights into the role of eicosanoids in osteoarthritis and elucidate the potential consequences of chronic pharmacologic COX-2 inhibition on the structural integrity of articular cartilage.
Inflammatory mediators
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