Pain Characteristics and Biomarkers in Treatment Approaches for Osteoarthritis Pain

Figures & data

Figure 1. Pain characteristics and the progression of osteoarthritis.

This schematic summarizes various pain characteristics that may or may not be present in an individual patient with osteoarthritis pain over the course of the disease. Pink/blue bars represent possible shifts in nociceptive pain that a patient could experience. Characteristics observed in early osteoarthritis (pain on movement, episodic pain, localized pain) continue in later stages as new characteristics arise. Sensitization and centralization processes underlie possible shifts in nociceptive pain characteristics. Pain with neuropathic features (green bar) may also be present.

Table 1. Biomarkers associated with pain or joint degeneration in osteoarthritis.

Osteoarthritis measure	Type of biomarker	Biomarker	Association	Ref.
Pain severity^†	Inflammatory markers	IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IFN-γ, CRP, CXCL10, TNF-α	+	[56–59]
		TNF-α, IL-1β, IL-6	–	[61]
	Other cytokines	MMP-3, MMP-13, MCP-1, HMGB-1	+	[59,61–63]
		MDC	–	[59]
	Macrophage/immune markers	MT-1, MIF	+	[64,65]
	Cartilage/bone turnover	TIMP-1, CTX-II, COMP	+	[57,62,66,67]
	Growth factors	SCGF-β, VEGF, TGF-β2	+	[58,62,68]
	Adhesion molecules	sVCAM-1, sICAM-1	+	[62]
Joint degeneration, measured by radiographic imaging^‡	Inflammatory markers	IL-6, IL-8, IFN-γ, IL-1Ra, CXCL-1	+	[58,69]
		IL-1β, IL-6, CD8+ T cells	–	[61,70]
	Other cytokines	MMP-3, leptin, adiponectin	+	[62,70,71]
		MMP-9, MMP-13, adiponectin, HMGB-1	–	[63,70]
	Macrophage/immune markers	CD14	+	[72]
	Cartilage/bone turnover	TIMP-1, CTX-II	+	[62,67,73]
		PIIANP	–	[74]
	Growth factors	SCGF-β, VEGF, TGF-β2, TGF-β3	+	[58,62,68]
	Adhesion molecules	sVCAM-1, sICAM-1	+	[62]
Pain characteristics ^§
Pain on movement	Inflammatory markers	IL-6, IL-8, TNF-α	+	[56]
		IL-1β	–	[56]
Pain at rest	Inflammatory markers	TNF-α	+	[56]
Weight-bearing pain	Inflammatory markers	IL-8	+	[60]
	Cartilage/bone turnover	CTX-II	+	[67]
Sensitization	Protein biomarkers	CRPM	+	[75]
Centralization	Growth factors	BDNF	+	[76]

† Based on pain scale severity scores.

‡ Based on the Kellgren-Lawrence grading system.

§ Assessed using an 11-point Likert numeric rating scale with the questions: “What is the intensity of pain on movement today (signal knee)?” and “What is the intensity of pain at rest today (signal knee)?”

BDNF: Brain-derived neurotrophic factor; CD: Cluster of differentiation; COMP: Cartilage oligomeric matrix protein; CRP: C-reactive protein; CRPM: MMP-mediated breakdown of CRP; CTX-II: Carboxy terminal cross-linked telopeptide of type II collagen; CXCL: C-X-C motif ligand; HMGB-1, high-mobility group box 1; IFN: Interferon; IL: Interleukin; IL1Ra: Interleukin-1 receptor antagonist; MCP: Monocyte chemoattractant protein; MDC; Macrophage-derived chemokine; MIF: Macrophage migration inhibitory factor; MMP: Matrix metalloproteinase; MT: Metallothionein; PIIANP: N-propeptide of collagen IIA; SCGF: Stem cell growth factor; sICAM-1: Soluble intracellular adhesion molecule 1; sVCAM-1: Soluble vascular cell adhesion molecule 1; TGF: Transforming growth factor; TIMP: Tissue inhibitor of metallopeptidase inhibitor; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.

Table 2. Effects of analgesics on biomarkers with a demonstrated association with osteoarthritis pain severity or degree of joint degradation.

Analgesic	Type of biomarker	Biomarker	Source	Effect on biomarker	Ref.
Oral NSAID	Inflammatory markers	TNF-α, CRP, IL-6	Synovial fluid	↓	[28,104,109,111]
		IL-8	Serum	↓	[105,108]
	Cartilage/bone turnover	MMP-3	Synovial fluid	↓	[104]
		MMP-3, MMP-13	Serum	↓	[108]
		CTX-II	Urine	↓	[106–108]
	Growth factor	VEGF	Synovial fluid	↓	[111]
COX-2 inhibitor	Inflammatory markers	IL-6, TNF-α	Synovial fluid	↓	[28,109]

↓ Analgesic treatment associated with a decrease in biomarker levels.

COX-2: Cyclooxygenase 2; CRP: C-reactive protein; CTX-II: Carboxy terminal cross-linked telopeptide of type II collagen; IL: Interleukin; MMP: Matrix metalloproteinase; NSAID: Nonsteroidal anti-inflammatory drug; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.

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