Aggrecanase degradation of type III collagen is associated with clinical knee pain

Abstract

There is a lack of biochemical markers for non-invasive and objective assessment of symptomatic osteoarthritis (OA). Aggrecanase activity has been shown to be associated with joint deterioration and symptomatic disease through the degradation of extracellular matrix proteins, such as type III collagen. Our study aimed to identify and develop a novel biomarker by measuring an aggrecanase-mediated type III collagen neoepitope, and correlate levels of this biomarker with OA joint pain. Mass spectrometric analysis of purified type III collagen, degraded by the aggrecanase A Disintigrin and Metalloproteinase with Thrombospondin motif (ADAMTS), revealed a fragment generated by ADAMTS-1, -4 and -8. A monoclonal antibody was raised against the neoepitope of this fragment (COL3-ADAMTS) and a competitive ELISA was developed and tested; using serum samples from a cross-sectional cohort of patients with different degrees of knee OA (n = 261). The COL3/ADAMTS ELISA was technically robust and specific for the ADAMTS-1, -4 and -8 generated neoepitope. COL3/ADAMTS was released form cytokine stimulated synovial cultures, indicating a biologic link between the marker and synovium. In OA patients, serum COL3/ADAMTS was independently associated with pain scores (rho = -0.13-0.17, p < 0.05). This association was associated significantly with the presence of radiographic OA. Together, these data indicate that COL3/ADAMTS could be a marker of early osteoarthritis and the underlining pathology.

Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

“…These results are similar to previous results. Bay-Jensen reported that serum COL3/ ADAMTS was weakly associated with pain scores (r = − 0.13-0.17, p < 0.05) [44]. Sun compared MMP-3 and NRS but did not find any correlation [45].…”

Aberrantly hydroxymethylated differentially expressed genes and the associated protein pathways in osteoarthritis

“…In the 10 core genes, increased mRNA expression levels of COL1A1, COL1A2, COL2A1, COL3A1, COL5A2 genes have been reported in OA (Bay-Jensen et al, 2018; Jin et al, 2009; Karlsson et al, 2010; Hermansson et al, 2004). Studies have shown that increased secretion of type I collagen encoded by COL1A1 and COL1A2 homotrimers in OA can induce stenosis and unorganized collagen fibers in subchondral bone (Clements et al, 2009; Couchourel et al, 2009; Jin et al, 2009; Steinberg et al, 2017).…”

“…Type III collagen encoded by COL3A1, together with type I collagen, provides a structural framework for the synovium surrounding the synovial joint (Hu et al, 2017; Reichert et al, 2018). Upregulation of type III in OA leads to thickening of the synovial membrane and has potential as a biomarker for OA (Bay-Jensen et al, 2018). Type V collagen encoded by COL5A1 and COL5A2, as a member of group I collagen, is present in tissues containing type I collagen, and appears to regulate the assembly of shaped fibers composed of type I and type V collagen (Colombi et al, 2017; Willard et al, 2018).…”

The inflammatory speech of fibroblasts

“…In addition to aggrecan, ADAMTS4 can also cleave collagen type III. Ex vivo cultures indicate that most of the ADAMTS activity toward collagen type III cleavage is exerted by ADAMTS4 produced in the synovium and not in the cartilage, 232 suggesting a significant contribution of inflammatory cytokine‐activated synovial cells to ADAMTS expression and collagen breakdown. Degradative enzyme expression associated with OA synovial fibrosis pathogenesis are likely to promote other joint tissue destructive processes as a result of FLS responses to inflammatory and fibrotic signaling molecules.…”