Smoljan Ivana, Detel Dijana, Buljevic Suncica, Erjavec Igor, Marić Ivana
Department of Internal Medicine, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia.
Department of Cardiovascular Diseases, Clinical Hospital Center Rijeka, Kresimirova 42, 51000 Rijeka, Croatia.
Biomedicines. 2023 Aug 1;11(8):2161. doi: 10.3390/biomedicines11082161.
Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to chronic inflammation and corticosteroid treatment. Bone morphogenic protein 7 (BMP7) has a complex role in maintaining inflammation and bone remodeling but little is known about its anti-inflammatory potential in chronic colitis. We investigated the effect of systemically administered BMP7 and corticosteroids on the severity of inflammation, macrophage differentiation, and bone regeneration in a chronic IBD model.
Chronic colitis was induced in male Sprague Dawley rats via weekly administration of 2,4,6-trinitrobenzenesulfonic acid over 21 days following BMP7 or corticosteroid treatment for five days. The levels of serum and colon tissue inflammatory cytokines, RANKL/OPG system, as well as markers of macrophage polarization, were detected using RT-PCR, ELISA, or immunohistochemistry. Long bone and spine analyses were performed using microcomputed tomography (micro-CT).
The administration of BMP7 reduced the adverse effects of colitis and led to elevated OPG and RANK in the colon with a simultaneous decrease in TNF-α and an increase in IL-10 and TGF-β. Decreased expression of the M2 macrophage marker CD163 was found in the BMP7-treated rats compared with the colitis group, whereas the number of M1 marker iNOS-positive cells did not differ between the groups. As a result of the BMP7 treatment, morphometric parameters of trabecular bone increased, and increased trabecular separation noted in the colitis group did not appear.
We showed that BMP7 suppressed the inflammatory response in chronic colitis, mainly by shifting the cytokine balance and by triggering alterations in the RANKL/OPG system rather than through a macrophage polarization imbalance. In addition, considering the demonstrated effect of BMP7 on bone morphology and structure, it can be suggested that BMP7 plays a role in the managing of osteoporosis in chronic colitis, and thus, its therapeutic potential in the treatment of IBD should be further evaluated.
炎症性肠病（IBD）患者骨损伤风险增加，这一过程由RANKL/RANK/OPG系统控制，主要归因于慢性炎症和皮质类固醇治疗。骨形态发生蛋白7（BMP7）在维持炎症和骨重塑中具有复杂作用，但对其在慢性结肠炎中的抗炎潜力知之甚少。我们研究了全身给予BMP7和皮质类固醇对慢性IBD模型中炎症严重程度、巨噬细胞分化和骨再生的影响。
在雄性Sprague Dawley大鼠中，通过在BMP7或皮质类固醇治疗5天后，每周给予2,4,6-三硝基苯磺酸，持续21天来诱导慢性结肠炎。使用RT-PCR、ELISA或免疫组织化学检测血清和结肠组织炎症细胞因子、RANKL/OPG系统以及巨噬细胞极化标志物的水平。使用微计算机断层扫描（micro-CT）进行长骨和脊柱分析。
给予BMP7可减轻结肠炎的不良反应，导致结肠中OPG和RANK升高，同时TNF-α降低，IL-10和TGF-β升高。与结肠炎组相比，BMP7治疗的大鼠中M2巨噬细胞标志物CD163的表达降低，而M1标志物iNOS阳性细胞的数量在两组之间没有差异。BMP7治疗的结果是，小梁骨的形态计量参数增加，结肠炎组中观察到的小梁间距增加未出现。
我们表明，BMP7抑制慢性结肠炎中的炎症反应，主要是通过改变细胞因子平衡和触发RANKL/OPG系统的改变，而不是通过巨噬细胞极化失衡。此外，考虑到BMP7对骨形态和结构的已证实作用，可以认为BMP7在慢性结肠炎骨质疏松的管理中起作用，因此，其在IBD治疗中的治疗潜力应进一步评估。
