Background/Purpose

Parathyroid hormone-related protein (PTHrP) binds to the type 1 PTH receptor (PTH1R), a member of the superfamily of G protein-coupled receptors (GPCRs). Activation of PTH1R by PTHrP has been widely documented to maintain cartilage homeostasis. However, PTHrP also acts as a cytokine-like peptide and mediates multi-organ inflammation. PTHrP content is higher in osteoarthritis (OA) synovial fluid. Changes in PTHrP expression in a rabbit OA model indicate PTHrP involvement in late rather than early pathogenic events. Blockade of PTHrP prevents articular cartilage destruction in streptococcal cell wall-induced arthritis. Emerging data show that GPCRs play important roles in inflammation through Ga12/13-mediated NF-kappa B/cyclooxygenase 2 (COX2) signaling pathway. In present studies, the effects of chronic PTHrP treatment on hypertrophic differentiation and inflammatory gene expression in chondrocytes were investigated.

Methods

Mouse chondrogenic cells (ATDC5), which express PTH1R during their differentiation, were used to examine hypertrophic differentiation and inflammatory gene expression in response to chronic PTHrP treatment. ATDC5 differentiation was induced by addition of ITS (10 µg/ml insulin, 10 µg/ml transferrin, and 10 ng/ml sodium selenite) into the cell culture medium after cell confluence. The mRNA expression for hypertrophic differentiation and inflammatory genes was detected by quantitative real-time PCR. PTH1R activation was determined by measuring [³H]-adenine incorporation for cAMP accumulation.

 

Results

The cartilage nodules in cultures of ATDC5 cells were formed by day 30 after ITS treatment. PTHrP (10 nM) initially inhibited ITS-induced expression of type 10 collagen a1 (Col10a1) and matrix metalloproteinase 13 (MMP13) (hypertrophic differentiation markers). However, the prolonged and sustained PTHrP increased Col10a1 and MMP13 expression in the late stage of differentiation (hypertrophic cells). Chronic PTHrP treatment enhanced the mRNA expression of COX2, but inhibited adenylyl cyclase activity in the late stage of differentiated chondrocytes.

Conclusion

These data suggest that chronic PTHrP treatment promotes a specific switch of PTH1R signaling from Gas to Ga12/13 to induce hypertrophic differentiation and increase inflammatory gene expression. Locally produced PTHrP in OA synovial fluid may have a pathogenic role in diseased cartilage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chronic-pthrp-treatment-promotes-hypertrophic-differentiation-and-inflammatory-gene-expression-in-chondrocytes/