(A) Heatmap of PageRanks of the top differential TFs selected from pairwise comparisons between unstimulated FLS from hand, hip, and knee. Pathway enriched TFs are labeled. For example, cAMP-responsive element–binding protein 1 (CREB1) has the greatest importance in hand FLS. Important TFs are reflected by increased accessibility of loci containing the TF motif, increased TF expression, and increased predicted TF binding affinity of the identified motif within the open chromatin regions. (B) Intersection plot of differential regulators (TFs) and regulatees (DARs and DEGs that are regulated by the differential regulator). Top bars indicate all differential features for each pairwise comparison. Heatmap indicates shared differential comparisons. Side bars indicate number of features that are shared between comparisons. For example, hand versus hip has 115 TFs that were identified with differential PageRanks. Fifty-one of those differential TFs were also identified from hip versus knee. Blue, red, and green are used for hand versus knee, hand versus hip, and knee versus hip comparisons, respectively. (C) For each joint, differential TFs with the greatest PageRank score in that joint was visualized. Nodes are scaled by PageRank. For example, PATZ1 has differential PageRanks between hand versus hip and has the greatest PageRank in hand (fold change in PATZ1 PageRank for hand versus knee: 1.2; hand versus hip: 1.3; knee versus hip: 0.8). (D) Pathway enrichment analysis of TFs and regulatee DARs and DEGs between pairwise comparisons. The greatest bias toward FLS aggressiveness was observed in hand versus hip comparisons and least between hip versus knee comparisons. Hand versus hip and hand versus knee comparisons were enriched for proinflammatory, e.g., “MAP kinase activation” (P < 0.003 by hypergeometric distribution test), and proliferative pathways e.g., “Constitutive signaling by AKT1 E17K in cancer” (P < 0.006 by hypergeometric distribution test). (E) Visualization of selected features. Genome browser shows differential open chromatin regulatory loci (left) and box-and-whisker plots are DEGs as representative examples of differential proliferative and proinflammatory features. The box-and-whisker plots display the median (line), the interquartile range (IQR) for the first (Q1) and third (Q3) quartiles (box bounds), and error bars (Q1 – 1.5 × IQR [low] and Q3 + 1.5 × IQR [high]). Values outside of the minimum and maximum are considered outliers (solid circles). **P < 0.01, ***P < 0.005 by Wilcoxon’s test.