Abstract
Progranulin (PGRN) is an autocrine growth factor that exerts crucial roles within cartilage tissue; however, the molecular mechanisms underlying PGRN-mediated cartilage homeostasis remain elusive. In the present study, we investigated the role of PGRN in regulating chondrocyte homeostasis and its therapeutic potential for managing osteoarthritis (OA). We found that PGRN levels are significantly increased in human cartilage in mild OA and that its expression is decreased in the cartilage in severe OA. In vitro, treatment of primary rat chondrocytes with recombinant PGRN significantly enhanced the levels of collagen type II α 1 chain (COL2A1) and aggrecan, and attenuated TNFα-induced up-regulation of matrix metallopeptidase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) in chondrocytes. These effects were abrogated in SIRT1-/- cells, indicating a causative role of SIRT1 in the effects of PGRN on protein expression in chondrocytes. Mechanistically, PGRN increased SIRT1 expression and activity, which reduced the acetylation levels of SRY-box transcription factor (SOX9) and transcription factor P65 (P65) and thereby promoted nuclear translocation of SOX9 and inhibited TNFα-induced P65 nuclear accumulation to maintain chondrocyte homeostasis. In conclusion, our findings reveal a mechanism of action for PGRN that maintains cartilage homeostasis and supports the notion that PGRN up-regulation may be a promising strategy for managing OA.
Highlights
Osteoarthritis (OA) is the most prevalent disorder in joint disease, characterized by progressive loss of articular cartilage, synovial inflammation, and osteophyte formation [1], causing joint pain and disability in older adults
Immunohistochemistry analysis showed that PGRN levels were increased in human cartilage in mild OA, with PGRN-positive cells mainly observed in the superficial zone, while its expression was decreased in severe OA (Fig. 1b)
PGRN has been purified and identified as a growth factor from conditioned tissue culture media by several independent laboratories [26,27,28], suggesting it may act as an autocrine manner
Summary
To gain insight into the role of PGRN during OA development, we obtained normal cartilage of the femoral head from patients with femoral neck fracture without joint disease, the lateral femoral condyle with mild OA, and the medial femoral condyle with severe OA. Inhibition of SIRT1 by SIRT1 siRNA (the efficiency was validated by real-time PCR and Western blotting) (Fig. 2, i and j and Fig. S2c) dramatically repressed PGRN-mediated up-regulation of cartilage genes (Fig. 2, k–o and Fig. S2d), indicating that PGRN may promote COL2A1 and aggrecan expression and secretion via up-regulation of SIRT1. D, mRNA levels of col2a1, aggrecan, MMP13, ADAMTS5, and PGRN were examined by real-time PCR in articular cartilage. Our data indicated that PGRN could inhibit chondrocytes catabolism induced by TNFa by deacetylation and suppressing P65 nuclear accumulation via enhancing the level of SIRT1. Knockdown of PGRN inhibited the anabolism of chondrocytes as evidenced by a decrease in COL2A1 and aggrecan expression and secretion (Fig. 6, d–g), whereas it did not affect levels of catabolic markers, including MMP13 and ADAMTS5 (Fig. 6h and Fig. S4b)
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