INSERM UMR 1033 LYOS and University of Lyon I, Lyon, France.
University of Paul Sabatier Toulouse III, INSERM-CNRS U1043, CPTP, CHU Purpan, and Pierre Paul Riquet Hospital, Toulouse, France.
Arthritis Rheumatol. 2019 Nov;71(11):1801-1811. doi: 10.1002/art.41005. Epub 2019 Sep 30.
The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown.
ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATX ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays.
OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties.
Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.
类风湿关节炎（RA）的严重程度与破骨细胞（OC）过度活跃引起的骨侵蚀直接相关。尽管 RA 患者的炎症可能得到控制，但处于持续临床缓解或低疾病活动状态的患者可能仍会不断发生侵蚀，这支持需要使用能够长期抑制 OC 活性而不改变 OC 在骨重塑中生理功能的治疗方法。自分泌酶（ATX）有助于炎症，但它在骨侵蚀中的作用尚不清楚。
用药物抑制 ATX 靶向治疗，并用鼠 OC 中 Ennp2 基因的条件性失活（ΔATX）靶向治疗。在肿瘤坏死因子转基因（hTNF）小鼠和 K/BxN 血清转移诱导关节炎小鼠中研究关节炎和侵蚀性疾病。用脂多糖（LPS）诱导的炎症和雌激素剥夺分析系统骨丢失。通过组织学和微计算机断层扫描评估关节炎症和骨侵蚀。还在 OC 分化和活性测定中检查了 ATX 在 RA 中的作用。
炎症部位的 OC 过度表达 ATX。与 vehicle 治疗对照组相比，hTNF 小鼠中 ATX 的药物抑制显著减轻了局灶性骨侵蚀（减少 36%；P < 0.05）和系统性骨丢失（减少 43%；P < 0.05），而不影响滑膜炎症。OC 衍生的 ATX 被证明是 OC 骨吸收活性的关键因素，并在 TNF 或 LPS 存在下引起的炎症中上调。接受卵巢切除术的小鼠中 OC 中 ATX 的特异性缺失显著防止了 LPS 和 K/BxN 血清处理引起的系统性骨丢失和侵蚀（系统性骨丢失减少 30%[P < 0.01]；侵蚀减少 55%[P < 0.001]），而没有赋予骨保护特性。
我们的结果将 ATX 确定为一种新型 OC 因子，可特异性控制炎症诱导的骨侵蚀和系统性骨丢失。因此，ATX 抑制为预防 RA 患者骨侵蚀提供了一种新的治疗方法。
