Del Rio-Moreno Mercedes, Poudel Sher Bahadur, Stilgenbauer Lukas, Cordoba-Chacon Jose, Sadagurski Marianna, Kineman Rhonda D, Yakar Shoshana
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL, USA.
Geroscience. 2025 Jul 26. doi: 10.1007/s11357-025-01816-1.
Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) have been linked to osteoporosis and osteoarthritis (OA), where the prevalence of all increase with age. Many individuals with NAFLD also exhibit MetS, a condition that is now termed metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD spans from simple hepatic steatosis to hepatocyte ballooning and inflammation, termed metabolic dysfunction-associated steatohepatitis (MASH), which may occur with or without fibrosis. To delineate the contribution of liver injury to skeletal deterioration within the context of metabolic syndrome (MetS), we fed male mice a high-fat, cholesterol, and fructose (HFCF) diet that induces metabolic syndrome-associated steatohepatitis (MASH) and liver fibrosis, associated with moderate obesity but without profound insulin resistance. A nutrient-matched diet with high carbohydrates but low in fat, cholesterol, and fructose (LFCF), which induced steatosis in adult mice, served as the control. Micro-CT analysis of the femur of HFCF-fed mice that developed MASH with fibrosis revealed significant cortical thinning (reduced bone area and thickness), decreased trabecular thickness, and lower bone mineral density compared to LFCF-fed mice, with no liver fibrosis. In the knee joint, MASH with fibrosis was associated with subchondral bone loss, medial cartilage erosion, and elevated chondrocyte expression of iNOS, NLRP3, and β-galactosidase. Bulk RNA-seq of knee tissue identified 152 differentially expressed genes: interferon-related (Oas3, Nlrc5, Zbp1) and stress-response (Slc6a4, Alox12, Cirbp, Trpc6, Tap1, Ubash3, Nrg1) pathways were upregulated, while extracellular matrix organization pathways were downregulated. Our findings reveal a mechanistic connection between the degree of liver injury and deterioration of bone and joint integrity, pointing to a shared pathophysiological axis in MASLD and OA. Clinically, this raises the prospect that a single therapeutic, designed to modulate inflammation, or hepatic lipid metabolism, could be repurposed or developed to concurrently treat both steatohepatitis and osteoarthritic degeneration.
非酒精性脂肪性肝病（NAFLD）和代谢综合征（MetS）与骨质疏松症和骨关节炎（OA）有关，且它们的患病率均随年龄增长而增加。许多非酒精性脂肪性肝病患者也表现出代谢综合征，这种情况现在被称为代谢功能障碍相关脂肪性肝病（MASLD）。MASLD范围从单纯性肝脂肪变性到肝细胞气球样变和炎症，即代谢功能障碍相关脂肪性肝炎（MASH），其可能伴有或不伴有纤维化。为了在代谢综合征（MetS）背景下阐明肝损伤对骨骼退化的影响，我们给雄性小鼠喂食高脂肪、高胆固醇和高果糖（HFCF）饮食，这种饮食会诱发与代谢综合征相关的脂肪性肝炎（MASH）和肝纤维化，伴有中度肥胖但无严重胰岛素抵抗。一种营养匹配但碳水化合物含量高而脂肪、胆固醇和果糖含量低的饮食（LFCF），其可在成年小鼠中诱发脂肪变性，用作对照。对出现伴有纤维化的MASH的HFCF喂养小鼠的股骨进行显微CT分析发现，与无肝纤维化的LFCF喂养小鼠相比，其皮质显著变薄（骨面积和厚度减少）、小梁厚度降低且骨密度较低。在膝关节中，伴有纤维化的MASH与软骨下骨丢失、内侧软骨侵蚀以及诱导型一氧化氮合酶（iNOS）、NLRP3和β-半乳糖苷酶的软骨细胞表达升高有关。膝关节组织的大量RNA测序确定了152个差异表达基因：干扰素相关（Oas3、Nlrc5、Zbp1）和应激反应（Slc6a4、Alox12、Cirbp、Trpc6、Tap1、Ubash3、Nrg1）途径上调，而细胞外基质组织途径下调。我们的研究结果揭示了肝损伤程度与骨和关节完整性恶化之间的机制联系，表明MASLD和OA存在共同的病理生理轴。临床上，这增加了一种可能性，即设计一种旨在调节炎症或肝脏脂质代谢的单一疗法，可以重新利用或开发，以同时治疗脂肪性肝炎和骨关节炎性退变。
