Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, Langone Orthopedic Hospital, 550 1st Avenue, New York, NY, 10016, USA.
Department of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital MS 8233, 425 South Euclid Avenue, St. Louis, MO, 63110, USA.
Arthritis Res Ther. 2021 Apr 8;23(1):104. doi: 10.1186/s13075-021-02477-z.
Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice.
The effects of Postn deficiency were studied in two murine experimental OA models using Postn (n = 32) and littermate wild-type (wt) mice (n = 36). Post-traumatic OA was induced by destabilization of the medial meniscus (DMM) in 10-week-old mice (n = 20); age-related OA was analyzed in 24-month-old mice (n = 13). Cartilage degeneration was assessed histologically using the OARSI scoring system, and synovitis was evaluated by measuring the synovial lining cell layer and the cells density in the synovial stroma. Bone changes were measured by μCT analysis. Serum levels of Postn were determined by ELISA. Expression of Postn and collagenase-3 (MMP-13) was measured by immunostaining. RNA-seq was performed on chondrocytes isolated from 21-day old Postn (n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout.
Postn mice exhibited significantly reduced cartilage degeneration and OARSI score relative to wt mice in post-traumatic OA after 8 weeks (maximum: 2.37 ± 0.74 vs. 4.00 ± 1.20, P = 0.011; summed: 9.31 ± 2.52 vs. 21.44 ± 6.01, P = 0.0002) and spontaneous OA (maximum: 1.93 ± 0.45 vs. 3.58 ± 1.16, P = 0.014; summed: 6.14 ± 1.57 vs. 11.50 ± 3.02, P = 0.003). Synovitis was significantly lower in Postn mice than wt only in the DMM model (1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039). Postn mice also showed lower trabecular bone parameters such as BV/TV, vBMD, Tb.Th, and Tb.N and high Tb. Sp in both models. Postn mice had negligible levels of serum Postn compared with wt. Immunofluorescent studies of cartilage indicated that Postn mice expressed lower MMP-13 levels than wt mice. RNA-seq revealed that cell-cell-adhesion and cell-differentiation processes were enriched in Postn mice, while those related to cell-cycle and DNA-repair were enriched in wt mice.
Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA.
骨膜蛋白（Postn）在软骨和骨中的水平升高与骨关节炎（OA）有关。然而，尚不清楚 Postn 功能丧失是否可以延迟或预防 OA 的发展。在这项研究中，我们试图更好地了解 Postn 在 OA 发展中的作用，并评估 Postn 缺乏对小鼠创伤后和年龄相关性 OA 的功能影响。
使用 Postn（n=32）和同窝野生型（wt）小鼠（n=36）研究了 Postn 缺乏的影响。在 10 周大的小鼠中通过不稳定内侧半月板（DMM）诱导创伤后 OA（n=20）；在 24 个月大的小鼠中分析年龄相关性 OA（n=13）。使用 OARSI 评分系统通过组织学评估软骨退化，通过测量滑膜衬里细胞层和滑膜基质中的细胞密度来评估滑膜炎。通过 μCT 分析测量骨变化。通过 ELISA 测定血清 Postn 水平。通过免疫染色测量 Postn 和胶原酶-3（MMP-13）的表达。对从小鼠分离的 21 天龄 Postn（n=3）和 wt 小鼠（n=3）的软骨细胞进行 RNA-seq，以发现由 Postn 敲除改变的基因和途径。
与 wt 小鼠相比，Postn 小鼠在创伤后 OA 后 8 周时（最大值：2.37±0.74 对 4.00±1.20，P=0.011；总和：9.31±2.52 对 21.44±6.01，P=0.0002）和自发性 OA（最大值：1.93±0.45 对 3.58±1.16，P=0.014；总和：6.14±1.57 对 11.50±3.02，P=0.003）的软骨退化和 OARSI 评分明显降低。只有在 DMM 模型中，Postn 小鼠的滑膜炎才明显低于 wt 小鼠（1.88±1.01 对 3.17±0.63；P=0.039）。Postn 小鼠在两种模型中还表现出较低的小梁骨参数，如 BV/TV、vBMD、Tb.Th 和 Tb.N 以及较高的 Tb.Sp。Postn 小鼠的血清 Postn 水平与 wt 相比微不足道。软骨的免疫荧光研究表明，Postn 小鼠的 MMP-13 水平低于 wt 小鼠。RNA-seq 显示细胞-细胞粘附和细胞分化过程在 Postn 小鼠中富集，而与细胞周期和 DNA 修复相关的过程在 wt 小鼠中富集。
Postn 缺乏可预防 DMM 诱导的创伤后和自发性年龄相关性 OA。RNA-seq 的发现需要进一步研究，以更好地了解 Postn 的机制作用及其在 OA 中的潜在治疗靶点。
