Table 1.

Summary of various types of treatment involving DAPMs examined in the study.

Treatments (DAMPs/Fn-f/proinflammatory cytokines)			Doses		Downstream effector tested	Summary of results	Figure number
Individual or undefined	Synthetic	fMLF	1 nM	10 nM	MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) Moderate upregulation of pro-MMP-13 only induced in bovine cells (2) No detectable upregulation of active form of MMP-13 or of other tested effectors	1, 3(a), 3(b), 4, 5(a)
		CpG DNA	10 μg/mL
		rh HMGB1	10 nM		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS		1, 2(a), 2(b), 2(c), 3(a), 3(b), 4, 5(a), 5(b)
		rhIL-1β	10 ng/mL		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	Strong upregulation of tested effectors	1, 2(a), 3(b), 4(b), 5(b)
		rbTNF-α	100 ng/mL		MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS		2(b), 3(a), 3(b), 4(b), 5(b)
Individual or undefined	Nonsynthetic	N-terminal 29 kDa Fn-f	300 nM		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	Strong upregulation of tested effectors except iNOS	2(a), 3(a), 3(b), 4(a), 5(b)
		Injured cartilage-conditioned media	Day 1 postinjury		MMP-3	Strong upregulation of MMP-3	2(c)
Combined	Paired	MTDs	10 μg/mL CpG DNA + 1 nM fMLF	10 μg/mL CpG DNA + 10 nM fMLF	MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	No detectable upregulation of tested effectors	1, 2(a), 2(b), 2(c), 3(a), 3(b), 4, 5(a), 5(b)
		Fn-f with individual DAMPs or proinflammatory cytokines	300 nM Fn-f + 10 nM HMGB1		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) Strong upregulation of tested effectors (2) Marked synergism between Fn-f and cytokines observed in MMP-3 upregulation (3) In human cells, moderate synergism observed between HMGB1 and Fn-f on upregulating MMP-3, MMP-13, and ADAMTS-5	2(a), 3(a), 4, 5(b)
			300 nM Fn-f + 10 ng/mL IL-1β
			300 nM Fn-f + 100 ng/mL TNF-α
		Proinflammatory cytokines or with individual DAMPs	10 ng/mL IL-1β + 100 ng/mL TNF-α		MMP-3	(1) IL-1β and TNF-α induced the most MMP-3 protein expression (2) Moderate synergism shown between TNF-a and HMGB1	2(b)
			100 ng/mL TNF-α + 10 nM HMGB1
			10 ng/mL IL-1β + 10 nM HMGB1		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	Strong synergism shown between HMGB1 and IL-1β on upregulating MMP-3, MMP-13, ADAMTS-5, ADAM-8, or iNOS	2(a), 2(b), 3(b), 4(b), 5(b)
Combined	Triple	MTDs with Fn-f or proinflammatory cytokines	10 μg/mL CpG DNA + 10 nM fMLF + 10 nM HMGB1		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) In bovine cells, moderate upregulation of pro-MMP-13 induced weaker effect in human cells (2) No detectable upregulation of active MMP-13 or other tested effectors	2(a), 2(b), 3(a), 3(b), 4, 5(b)
			10 μg/mL CpG DNA + 10 nM fMLF + 300 nM fMLF		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) Strong upregulation of tested effectors expect iNOS (2) Synergism not observed	2(a), 3(a), 4(a), 5(b)
			10 μg/mL CpG DNA + 10 nM fMLF + 10 ng/mL IL-1β		MMP-1, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) Strong upregulation of tested effectors (2) Moderate synergism observed on upregulating MMP-13 or iNOS	2(b), 3(a), 4(b), 5(b)
			10 μg/mL CpG DNA + 10 nM fMLF + 100 ng/mL TNF-α		MMP-3	HMGB1 and IL-1β showed much stronger synergism with TNF-α than MTDs did	2(b)
		Proinflammatory cytokines with HMGB1 or Fn-f	10 nM HMGB1 + 10 ng/mL IL-β + 100 ng/mL TNF-α
			300 nM Fn-f + 10 ng/mL IL-β + 100 ng/mL TNF-α		MMP-1, MMP-3, MMP-13, ADAMTS-5	Strong upregulation of tested effectors	2(a)
Combined	Quaternary	DAMPs with Fn-f or proinflammatory cytokines	10 μg/mL CpG DNA + 10 nM fMLF + 10 nM HMGB1 + 300 nM Fn-f		MMP-1, MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	Strong upregulation of tested effectors except iNOS	2(a), 3(a), 4(a), 5(b)
			10 μg/mL CpG DNA + 10 nM fMLF + 10 nM HMGB1 + 10 ng/mL IL-1β		MMP-3, MMP-13, ADAMTS-5, ADAM-8, iNOS	(1) Strong upregulation of tested effectors (2) Marked synergism observed on upregulating MMP-3, MMP-13, or iNOS	3(b), 4(b), 5(b)
			10 μg/mL CpG DNA + 10 nM fMLF + 10 ng/mL IL-1β + 100 ng/mL TNF-α		MMP-3	Strong upregulation of MMP-3 observed but no synergism between MTDs and cytokines detected	2(b)