Session Title: Biology and Pathology of Bone and Joint - Poster I
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Osteoarthritis (OA) is the most common degenerative disease of the joints, affecting nearly 30 million Americans. It is characterized by a change in chondrocyte phenotype. The default route of chondrocyte differentiation is terminal differentiation, hypertrophy, apoptosis, and bone formation. In healthy articular cartilage, this default route is somehow blocked to obtain permanent cartilage. In OA, this block is lifted resulting in chondrocyte terminal differentiation characterized by a decrease in production of extracellular matrix proteins (type 2 collagen and aggrecan) and an increase in production of type 10 collagen, matrix metalloproteinase 13 (MMP13), and the transcription factor Runx2. Follistatin-like protein 1 (FSTL-1) is a protein produced by articular chondrocytes. Its expression is decreased in OA. Homozygous FSTL1 knockout (KO) mice display hypocellular cartilage as well as extensive skeletal defects. We therefore sought to determine whether loss of FSTL-1 in OA contributes to disease and whether increasing FSTL-1 expression will slow or reverse OA.
Methods: FSTL-1 expression in OA and healthy human cartilage was evaluated by immunofluorescence. Cartilage was evaluated in sectioned knee joints from FSTL-1 KO mice by staining with safranin-O. In vitro experiments were performed with human articular chondrocytes immortalized with the human telomerase gene and HPV oncogenes E6 and E7. The cells were transduced with a lentivirus encoding human FSTL-1 shRNA, or with an adenovirus encoding FSTL-1. Quantitative gene expression analysis was performed using real-time PCR for MMP13, aggrecan, collagens type 2 (COL2A) and type 10 (COL10A). Protein extracts from chondrocyte pellets were analyzed for Sox9 and phospho (p)-Smad3 by Western blotting.
Results: FSTL-1 expression was reduced in the OA chondrocytes. In FSTL-1 KO mice, a marked reduction in articular cartilage cellularity, cartilage thickness, and matrix proteoglycan content was observed at 12 months of age. Downregulation of FSTL-1 expression in TGFβ-stimulated human chondrocyte pellet cultures led to abnormally small pellets with reduced proteoglycan content. The chondrocytes displayed an OA-like phenotype characterized by increased MMP13, COL10A, Runx2, and reduced Sox9, COL2A, aggrecan, and p-Smad3 expression. Transduction of chondrocytes with an FSTL-1 transgene led to a substantial increase in expression of COL2A.
Conclusion: These studies demonstrate that FSTL-1 plays a critical role in maintaining healthy cartilage by blocking the default route of chondrocyte terminal differentiation. Furthermore, we have shown that restoring FSTL-1 expression in chondrocytes can reverse changes observed in OA.
To cite this abstract in AMA style:Chaly Y, Hostager B, Smith S, Hirsch R. Follistatin-like Protein 1 Is a Potent Regulator of Articular Chondrocytes in Osteoarthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/follistatin-like-protein-1-is-a-potent-regulator-of-articular-chondrocytes-in-osteoarthritis/. Accessed May 19, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/follistatin-like-protein-1-is-a-potent-regulator-of-articular-chondrocytes-in-osteoarthritis/