Development of Postoperative Pain in Patients with End-Stage Knee Osteoarthritis Is Associated with Upregulation of Genes Related to Extracellular Matrix Degradation, Inflammation, and Apoptosis Measured in the Peripheral Blood before Knee Surgery

Abstract

Osteoarthritis (OA) pain implies an indication for joint replacement in patients with end-stage OA. However, chronic postoperative pain is observed in 10–40% of patients with OA. Here, we identified genes whose expression in the peripheral blood before surgery could denote the risk of postoperative pain development. We examined the peripheral blood of 26 healthy subjects and 50 patients with end-stage OA prior to joint replacement surgery. Pain was evaluated before surgery using the visual analog scale (VAS) index and neuropathic pain questionnaires, Douleur Neuropathique 4 Questions (DN4) and PainDETECT questionnaires. Functional activity was assessed using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Three and six months after surgery, pain indices according to VAS of 30% and higher were considered. Metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)1 protein levels were measured using ELISA in the peripheral blood mononuclear cells (PBMCs). Total RNA isolated from whole blood was analysed using quantitative real-time RT-PCR for caspase-3, MMP-9, TIMP1, cathepsins K and S, tumour necrosis factor (TNF)α, interleukin (IL)-1β, and cyclooxygenase (COX)-2 gene expression. Seventeen patients reported post-surgical pain. Expression of cathepsins K and S, caspase-3, TIMP1, IL-1β, and TNFα genes before surgery was significantly higher in these patients compared to pain-free patients with OA. Receiver-operating characteristic (ROC) curve analyses confirmed significant associations between these gene expressions and the likelihood of pain development after arthroplasty. High baseline expression of genes associated with extracellular matrix destruction (cathepsins S and K, TIMP1), inflammation (IL-1β, TNFα), and apoptosis (caspase-3) measured in the peripheral blood of patients with end-stage OA before knee arthroplasty might serve as an important biomarker of postoperative pain development.

Differences in Synovial Cytokine Profile Associated with Long-Term Clinical Outcomes in Patients with Knee Osteoarthritis Undergoing Corrective Osteotomy with Platelet-Rich Plasma or Stromal Vascular Fraction Post-Treatments

“…Pain sensation and clinical manifestations of the OA disease were previously associated with an increase in cytokine expression [ 24 , 25 ]. Therefore, a significant decrease in SF concentrations of IL-6 and IP-10 in case of PRP treatment as well as TNFα, IL-15, Flt-3L, MIP-1β, RANTES, and VEGF in case of SVF injection in association with reduction of pain scores that were observed in our study further support this finding.…”

Associations between markers of inflammation and altered pain perception mechanisms in people with knee osteoarthritis: a systematic review

“… 46 In patients with end-stage OA, higher neuropathic-like pain scores on painDETECT and DN4 Questionnaires were found to be positively correlated with gene expression of TNF-α and IL-1β. 48 Taking these results together, there is conflicting evidence on a possible association between inflammatory cytokines and neuropathic-like pain (conclusion level 4).…”

“…Only one study reported consistent significant results on blood levels of proinflammatory cytokines which were found to be correlated with presence of neuropathic-like pain, but the correlation values did not go beyond the moderate level (ie, r values ≤0.5). 48 However, the study sample included only patients with advanced knee OA and the analyses did not include potential confounders. 48 Importantly, the results of Radojčić et al revealed that the association between synovial fluid IL-6 and neuropathic-like pain was explained by synovitis.…”

Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments

“…As OA is a multifactorial disease, the underlying pathological process is closely associated with alterations of various transcripts [ 6 , 7 , 8 , 9 , 10 ], including noncoding RNA species (ncRNAs), especially small ncRNAs, which are <200 nucleotides (nt) in length. It has been reported that unique small ncRNA expression signatures are believed not only to characterize specific types of cells, but also to be indicative of particular diseases [ 11 ].…”