Secreted factors from synovial fibroblasts immediately regulate gene expression in articular chondrocytes

TY - JOUR

T1 - Secreted factors from synovial fibroblasts immediately regulate gene expression in articular chondrocytes

AU - Bonitz, Martin

AU - Schaffer, Christiane

AU - Amling, Michael

AU - Poertner, Ralf

AU - Schinke, Thorsten

AU - Jeschke, Anke

PY - 2019/5/25

Y1 - 2019/5/25

N2 - Although articular cartilage degeneration in osteoarthritis represents a major public health problem, there is still no molecular approach to prevent this pathology by blocking specific molecules. We have previously applied genome-wide expression analyses with porcine samples to identify specific markers of either growth plate or articular cartilage. Since the molecular differences were also found in cultured chondrocytes derived from both sites, we utilized primary porcine articular chondrocytes (PPACs) for the present study and analyzed, if and how they respond to synoviocyte-derived molecules. PPACs were treated by conditioned medium from porcine synovial fibroblasts (SF-CM) for 2, 6 and 24 h. Gene expression was subsequently monitored by qRT-PCR and microarray analysis. We found that short-term administration of SF-CM to PPACs significantly reduced expression of chondrocyte markers, while it induced expression of SDC4, encoding syndecan-4, a positive regulator of articular cartilage breakdown. Consistently, expression of MMP3, a putative downstream effector of syndecan-4 was strongly induced by SF-CM in PPACs. We identified an MMP3-inducing fraction in the range of 40 kDa after gel filtration, and we confirmed our findings in three-dimensional PPAC cultures, where SF-CM also reduced the glycosaminoglycan content. Taken together, our data suggest that synovial fibroblasts secrete one or more molecule(s) that activate specific signaling events in articular chondrocytes. Identifying a responsible ligand receptor pair(s) might pave the way to develop molecular therapies to reduce the severity of osteoarthritis.

AB - Although articular cartilage degeneration in osteoarthritis represents a major public health problem, there is still no molecular approach to prevent this pathology by blocking specific molecules. We have previously applied genome-wide expression analyses with porcine samples to identify specific markers of either growth plate or articular cartilage. Since the molecular differences were also found in cultured chondrocytes derived from both sites, we utilized primary porcine articular chondrocytes (PPACs) for the present study and analyzed, if and how they respond to synoviocyte-derived molecules. PPACs were treated by conditioned medium from porcine synovial fibroblasts (SF-CM) for 2, 6 and 24 h. Gene expression was subsequently monitored by qRT-PCR and microarray analysis. We found that short-term administration of SF-CM to PPACs significantly reduced expression of chondrocyte markers, while it induced expression of SDC4, encoding syndecan-4, a positive regulator of articular cartilage breakdown. Consistently, expression of MMP3, a putative downstream effector of syndecan-4 was strongly induced by SF-CM in PPACs. We identified an MMP3-inducing fraction in the range of 40 kDa after gel filtration, and we confirmed our findings in three-dimensional PPAC cultures, where SF-CM also reduced the glycosaminoglycan content. Taken together, our data suggest that synovial fibroblasts secrete one or more molecule(s) that activate specific signaling events in articular chondrocytes. Identifying a responsible ligand receptor pair(s) might pave the way to develop molecular therapies to reduce the severity of osteoarthritis.

KW - Animals

KW - Cartilage, Articular/metabolism

KW - Chondrocytes/metabolism

KW - Fibroblasts/metabolism

KW - Gene Expression

KW - Gene Expression Regulation/genetics

KW - Growth Plate

KW - Matrix Metalloproteinase 3/genetics

KW - Osteoarthritis

KW - Primary Cell Culture

KW - Swine

KW - Syndecan-4/genetics

KW - Synovial Fluid/metabolism

KW - Synovial Membrane

U2 - 10.1016/j.gene.2019.02.065

DO - 10.1016/j.gene.2019.02.065

M3 - SCORING: Journal article

C2 - 30825594

VL - 698

SP - 1

EP - 8

JO - GENE

JF - GENE

SN - 0378-1119

ER -