Osteoarthritis (OA) is the most common musculoskeletal disorder. Although joint replacement remains the standard of care for knee OA patients, knee joint distraction (KJD), which works by temporarily off-loading the joint for 6–8 weeks, is becoming a novel joint-sparing alternative for younger OA sufferers. The biological mechanisms behind KJD structural improvements remain poorly understood but likely involve joint-resident regenerative cells including multipotent stromal cells (MSCs). In this study, we hypothesized that KJD leads to beneficial cartilage-anabolic and anti-catabolic changes in joint-resident MSCs and investigated gene expression profiles of synovial fluid (SF) MSCs following KJD as compared with baseline. To obtain further insights into the effects of local biomechanics on MSCs present in late OA joints, SF MSC gene expression was studied in a separate OA arthroplasty cohort and compared with subchondral bone (SB) MSCs from medial (more loaded) and lateral (less loaded) femoral condyles from the same joints. In OA arthroplasty cohort (n = 12 patients), SF MSCs expressed lower levels of ossification- and hypotrophy-related genes [bone sialoprotein (IBSP), parathyroid hormone 1 receptor (PTH1R), and runt-related transcription factor 2 (RUNX2)] than did SB MSCs. Interestingly, SF MSCs expressed 5- to 50-fold higher levels of transcripts for classical extracellular matrix turnover molecules matrix metalloproteinase 1 (MMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and tissue inhibitor of metalloproteinase-3 (TIMP3), all (p < 0.05) potentially indicating greater cartilage remodeling ability of OA SF MSCs, compared with SB MSCs. In KJD cohort (n = 9 patients), joint off-loading resulted in sustained, significant increase in SF MSC colonies’ sizes and densities and a notable transcript upregulation of key cartilage core protein aggrecan (ACAN) (weeks 3 and 6), as well as reduction in pro-inflammatory C–C motif chemokine ligand 2 (CCL2) expression (weeks 3 and 6). Additionally, early KJD changes (week 3) were marked by significant increases in MSC chondrogenic commitment markers gremlin 1 (GREM1) and growth differentiation factor 5 (GDF5). In combination, our results reveal distinct transcriptomes on joint-resident MSCs from different biomechanical environments and show that 6-week joint off-loading leads to transcriptional changes in SF MSCs that may be beneficial for cartilage regeneration. Biomechanical factors should be certainly considered in the development of novel MSC-based therapies for OA.

中文翻译：

---

晚期膝骨关节炎和膝关节牵引后滑液多能基质细胞的基因表达特征

骨关节炎（OA）是最常见的肌肉骨骼疾病。尽管关节置换仍然是膝关节 OA 患者的标准护理，但膝关节牵引 (KJD) 通过暂时减轻关节 6-8 周的负荷来发挥作用，正成为年轻 OA 患者的一种新型关节保留替代方案。KJD 结构改进背后的生物学机制仍然知之甚少，但可能涉及联合驻留再生细胞，包括多能基质细胞 (MSC)。在这项研究中，我们假设 KJD 导致关节驻留 MSC 中有益的软骨合成代谢和抗分解代谢变化，并研究了 KJD 后滑液 (SF) MSC 与基线相比的基因表达谱。为了进一步了解局部生物力学对晚期 OA 关节中存在的 MSC 的影响，在单独的 OA 关节成形术队列中研究了 SF MSC 基因表达，并将其与来自相同关节的内侧（负荷较大）和外侧（负荷较小）股骨髁的软骨下骨 (SB) MSC 进行了比较。在 OA 关节置换术队列（n = 12 名患者）中，SF MSCs 表达较低水平的骨化和营养不良相关基因 [骨唾液蛋白 (IBSP)、甲状旁腺激素 1 受体 (PTH1R) 和矮小相关转录因子 2 (RUNX2)]比SB MSC。有趣的是，SF MSC 表达的经典细胞外基质转换分子基质金属蛋白酶 1 (MMP1)、具有血小板反应蛋白基序 5 (ADAMTS5) 和金属蛋白酶组织抑制剂 3 (TIMP3) 的去整合素和金属蛋白酶的转录水平高 5 至 50 倍, 所有 (p < 0.05) 可能表明 OA SF MSCs 具有更强的软骨重塑能力，与 SB 间充质干细胞相比。在 KJD 队列（n = 9 名患者）中，关节卸载导致 SF MSC 集落的大小和密度持续显着增加，以及关键软骨核心蛋白聚集蛋白聚糖 (ACAN) 的显着转录上调（第 3 周和第 6 周），如以及促炎性 C-C 基序趋化因子配体 2 (CCL2) 表达的减少（第 3 周和第 6 周）。此外，早期 KJD 变化（第 3 周）的特点是 MSC 软骨形成标记物 gremlin 1 (GREM1) 和生长分化因子 5 (GDF5) 显着增加。结合起来，我们的结果揭示了来自不同生物力学环境的联合驻留 MSC 的不同转录组，并表明 6 周的联合卸载导致 SF MSC 的转录变化，这可能有利于软骨再生。