Adamts5 (aggrecanase‐2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines

Abstract

ADAMTS5 (aggrecanase-2) is an extracellular matrix-degrading protease implicated in cartilage destruction in arthritis. Our goals were to determine expression sites of Adamts5 in the murine musculoskeletal system and in an ex vivo joint inflammation model. In mice with an intragenic LacZ reporter controlled by the Adamts5 promoter, b-galactosidase staining was used to identify Adamts5 expressing cells. Mice expressing one wild-type Adamts5 allele were used to determine distribution of Adamts5 mRNA, cleaved aggrecan and versican, and the ADAMTS5 activating enzymes furin and PACE4. Quantitative RT-PCR and immunoblotting were used to validate the immunohistochemistry results. Adamts5 was expressed in mouse synovium, tenosynovium, bone marrow sinusoids, tendons, ligaments, ligament insertions, periosteal cells, and bone vasculature. In knee joint explants treated with IL-1a and TNFa, Adamts5 expression was induced in tenocytes, synovium, and in patellar, but not femoral or tibial articular cartilage. In contrast, increased proteoglycan breakdown in tibial and femoral articular cartilage was associated with increased immunohistochemical staining of PACE4 and furin. These studies identify diverse cell types in the musculoskeletal system that express Adamts5. They also suggest that Adamts5 induction in joint components other than cartilage, and its post-translational activation by PACE4 and/or furin may be important in the pathophysiology of arthritis. ß

Connexin43 Mediated Delivery of ADAMTS5 Targeting siRNAs from Mesenchymal Stem Cells to Synovial Fibroblasts

“…While synovial produce ADAMTS5 and ADAMTS5 levels in the synovial fluid are high in OA, several cell types in the joint can express ADAMTS5 [38–40]. However, synovial but not articular chondrocyte expression of ADAMTS5 has been demonstrated following inflammatory cytokine treatment in a murine knee joint explant model [40]. It is becoming increasingly clear that OA is a disease of the total joint and a more holistic approach of targeting numerous cell types may be essential to mitigating joint degeneration.…”

Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings

“…33 ADAMTS4, like MMP13, is induced by inflamma tory and catabolic cytokines such as IL1. The results of studies with human cartilage explants and chondro cytes suggest that ADAMTS5 is not regulated by these cytokines, 34,35 whereas murine experiments in vivo have demonstrated upregulation of ADAMTS5 by catabolic cytokines. 35 Syndecan4 (SYND4), a transmembrane, heparan sulfate proteoglycan that is expressed strongly Key points ■ The molecular mechanisms of cartilage breakdown in rheumatoid arthritis (RA) and osteoarthritis (OA) show considerable overlap, particularly with respect to matrix-degrading enzymes, but also with respect to some inflammatory mediators ■ The loss of phenotypic stability of articular chondrocytes, and initiation of a programme resembling aspects of embryonic endochondral ossification, could explain important features of OA ■ In contrast to OA, RA is associated with a stable, tumour-like activation of fibroblast-like synoviocytes that mediate the destruction of articular cartilage through directed invasion ■ Cartilage has active roles in OA and RA as a signalling scaffold harbouring bioactive matrix components and soluble factors, which interact with embedded chondrocytes and are released upon cartilage degradation in hypertrophic chondrocytes during embryonic devel opment, and that is also expressed during OA, contrib utes to the regulation of ADAMTS5 activity.…”

Subtilisin‐like proprotein convertase paired basic amino acid‐cleaving enzyme 4 is required for chondrogenic differentiation in ATDC5 cells

“…On the other hand, a recent study has shown that PACE4 is responsible for proteolytic activation of aggrecanases in osteoarthritic and cytokine‐stimulated cartilage . Interestingly, the expression of PACE4 was increased in cartilage by inflammatory cytokines , although the mechanism of this remains unclear. Further study will clarify the mechanism of spatial and temporal transcriptional regulation of PACE4 in chondrocyte differentiation and osteoarthritis.…”