Department of Biomedicine and Prevention, Tor Vergata University of Rome, Via Montpellier 1, 00133, Rome, Italy.
Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
J Transl Med. 2019 Apr 10;17(1):118. doi: 10.1186/s12967-019-1868-5.
Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition.
Vastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis.
We found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment.
Results obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.
针对导致骨质疏松症 (OP) 和骨关节炎 (OA) 的新分子途径是药物发现的热门话题。 簇蛋白 (CLU) 是一种参与炎症、增殖、细胞死亡、肿瘤疾病、阿尔茨海默病和衰老的糖蛋白。本研究重点研究 CLU 在影响 OP-OA 情况下肌肉质量减少和纤维衰老中的表达和作用。
从 20 名接受脆性髋部骨折手术的 OP 女性和 20 名接受髋关节骨关节炎关节置换术的女性中采集股外侧肌活检。
我们发现，在与白细胞介素 6 (IL6) 和组蛋白 H4 乙酰化水平密切相关的 OP 退变纤维中，CLU 过度表达。相反，在 OA 肌肉组织中，我们观察到 CLU 表达较弱，但没有核组蛋白 H4 乙酰化。离体研究表明，与 OA 相比，OP 中的 CLU 过表达（p<0.001）。CLU 处理分离的 OP 和 OA 成肌细胞显示：与 OA 相比，OP 成肌细胞的增殖、形态变化、组蛋白 H4 乙酰化增加和肌生成素 (MYOG) 激活增加（p<0.001）。在 OP 条件下，siRNA 对 CLU 的功能敲低可恢复增殖成肌细胞的能力，并通过明显上调转谷氨酰胺酶 2 (TGM2) 修复组织损伤。我们还观察到 CX3CR1 表达下调，随后炎症浸润招募受损。
研究结果表明 CLU 在 OP 中通过影响成肌细胞终末分化、肌肉细胞分化和衰老的表观遗传调控，发挥潜在作用。此外，CLU 沉默表明其在调节组织损伤修复和炎症中的作用，提出其作为肌肉变性的新诊断标志物和 OP 相关肌肉减少症的潜在治疗靶点。
