Session Type: Abstract Submissions (ACR)
Osteoarthritis (OA) is the most common joint disease. Among the earliest lesions during OA development is disruption of the superficial zone (SZ) of articular cartilage. The SZ of articular cartilage contains adult mesenchymal progenitor cells and is unique in extracellular matrix composition. Recently, we found that the EFEMP1 gene encoding fibulin-3 is specifically expressed in SZ. However, the expression pattern of fibulin-3 in articular cartilage and its role is unknown. The objectives of this study were to examine fibulin-3 expression patterns in joint aging and OA and to investigate the role of fibulin-3 in OA pathogenesis.
Immunohistochemical analysis was performed on human and mouse knee cartilage to determine changes in fibulin-3 expression during joint aging and in OA. To examine the role of fibulin-3 in cartilage homeostasis, experimental OA was induced in wild type and fibulin-3-/-mice. The mice were euthanized 10 weeks after the knee surgery for histological analysis. To address whether fibulin-3 is involved in regulating chondrocyte differentiation, human articular chondrocytes were transfected with fibulin-3-specific siRNA. Cells were harvested at 48 hours and 72 hours for quantitative PCR and Western blot analyses. To further address the role of fibulin-3 during chondrogenesis, bone marrow mesenchymal stem cells (MSC) were transduced with lentivirus (LV) encoding EFEMP1 or control LV expressing LacZ, then MSC pellets were prepared and analyzed for chondrogenesis.
Fibulin-3 was specifically expressed in the SZ of normal cartilage in human and mouse knee joints. Fibulin-3 expression was intracellular and in the extracellular matrix (ECM) and declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin-3-/-mice compared with wild type mice. Fibulin-3 expression was high in MSC and decreased during chondrogenesis. Suppression of fibulin-3 by siRNA in MSC significantly increased SOX9, collagen II and aggrecan in articular chondrocytes, while the overexpression of fibulin-3 inhibited chondrogenesis in MSC.
We found that fibulin-3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin-3 regulates survival and differentiation of adult progenitor cells and its aging-related decline is an early event in OA pathogenesis. Preventing or restoring aging-associated loss of fibulin-3 in SZ chondrocytes has potential to delay or prevent onset of OA.
L. Y. Marmorstein,
M. K. Lotz,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibulin-3-in-joint-aging-and-osteoarthritis-pathogenesis/