Arthritis & Regenerative Medicine Laboratory, Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
The Rowett Institute and Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Osteoarthritis Cartilage. 2024 Dec;32(12):1552-1565. doi: 10.1016/j.joca.2024.07.006. Epub 2024 Aug 3.
Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.
Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with whole-body Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically.
The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα-expressing Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite the presence of synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity.
Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.
脂肪组织功能障碍伴发代谢综合征和超重会增加肥胖患者患骨关节炎（OA）的风险。脂肪营养不良综合征表现出与肥胖相似的全身代谢和炎症异常，但没有生物力学过载。在这里，我们使用脂肪营养不良小鼠模型来研究全身性和关节内脂肪组织功能障碍对膝关节的影响。
使用报告基因小鼠研究关节内脂肪组织的发育。通过条件性敲除（cKO）Gdf5 谱系细胞中的 Bscl2 生成关节内脂肪组织选择性脂肪营养不良的小鼠，并与全身性 Bscl2 敲除（KO）小鼠进行比较，后者具有普遍性脂肪营养不良和相关的全身代谢功能障碍。通过手术不稳定内侧半月板（DMM）诱导 OA，并用高脂肪饮食（HFD）诱导肥胖。通过定量 RT-PCR 分析基因表达，并用组织学方法分析组织。
髌下脂肪垫（IFP）与覆盖的皮下脂肪组织不同，它是从 Gdf5 表达的关节间区在胚胎后期建立的模板中发育而来的，在出生后不久，由来自表达 Pdgfrα的 Gdf5 谱系祖细胞的脂肪细胞随机出现而填充。尽管女性全身性 Bscl2 KO 小鼠发生自发性膝关节软骨损伤，但具有关节内脂肪营养不良的 Bscl2 cKO 小鼠并未发生这种情况，尽管存在滑膜增生和残留 IFP 的炎症。此外，DMM 后雄性 Bscl2 cKO 小鼠的软骨损伤没有恶化。然而，雌性 Bscl2 cKO 小鼠对 HFD 诱导肥胖导致的软骨损伤更为敏感。
我们的研究结果强调了全身代谢和炎症作用在破坏软骨稳态方面的普遍作用，关节内脂肪组织具有调节作用。
