Scimeca Manuel, Piccirilli Eleonora, Mastrangeli Francesca, Rao Cecilia, Feola Maurizio, Orlandi Augusto, Gasbarra Elena, Bonanno Elena, Tarantino Umberto
Multidisciplinary Study of the Effects of Microgravity on Bone Cells" Project, Spatial Biomedicine Center, Italian Space Agency (ASI), Via del Politecnico snc, 00133, Rome, Italy.
Anatomic Pathology Section, Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Via Montpellier 1, 00133, Rome, Italy.
J Transl Med. 2017 Feb 15;15(1):34. doi: 10.1186/s12967-017-1143-6.
Sarcopenia, osteoporosis and osteoarthritis are the most frequent musculoskeletal disorders affecting older people. The main aim of this study was to test the hypothesis that the balance between BMPs and myostatin pathways regulates the age-related muscle degeneration in OP and OA patients. To this end, we investigated the relationship among the expression of BMP-2/4-7, myostatin and phosphorylated Smads1-5-8 and the muscle quality, evaluated in term of fibers atrophy and satellite cells activity.
In this retrospective study, we collected 123 biopsies of vastus lateralis: 48 biopsies from patients who underwent hip arthroplasty for subcapital fractures of the femur (OP), 55 biopsies from patients who underwent hip arthroplasty for osteoarthritis (OA) and 20 biopsies from patients who underwent hip arthroplasty for high-energy hip fractures (CTRL). Muscle biopsies were fixed in 4% paraformaldehyde and paraffin embedded. Serial sections were used for morphometrical and immunohistochemical analysis (BMP/2/4-7, myostatin, Smads1-5-8, Pax7 and myogenin). In addition, 1 mm of muscle tissue of each patient was embedded in epon for ultrastructural study.
Morphometric data indicated an increase of the number of atrophic fibers in OP patients compare to OA. In line with these data, we found an high regenerative potential in muscle tissues of OA patients due to the significant amount of both Pax7 and myogenin positive satellite cells detected in OA group. In addition, our data showed the decrease of BMP2/4 and -7 expression in OP patients compared to both OA group and CTRL. Conversely, OP patients were characterized by high levels of myostatin expression. A different expression profile was also found for phosphorylated Smad1-5-8 between OP and OA patients. In particular, OP patients showed a low number of positive phosphorylated Smad1-5-8 nuclei.
The identification of molecular pathways involved in the pathogenesis of sarcopenia open new prospective for the development of drugs able to prevent/treat the muscle impairment that occur in elderly. Results here reported, highlighting the role of BMPs and myostatin pathways in physio-pathogenesis of human sarcopenia, allow us to propose human recombinant BMP-2/7 and anti-myostatin antibodies as a possible therapeutic option for the sarcopenia.
肌肉减少症、骨质疏松症和骨关节炎是影响老年人最常见的肌肉骨骼疾病。本研究的主要目的是验证以下假设：骨形态发生蛋白（BMPs）和肌肉生长抑制素信号通路之间的平衡调节骨质疏松症（OP）和骨关节炎（OA）患者与年龄相关的肌肉退化。为此，我们研究了BMP-2/4-7、肌肉生长抑制素和磷酸化Smad1-5-8的表达与肌肉质量之间的关系，并从纤维萎缩和卫星细胞活性方面进行评估。
在这项回顾性研究中，我们收集了123例股外侧肌活检样本：48例来自因股骨颈骨折接受髋关节置换术的患者（OP组），55例来自因骨关节炎接受髋关节置换术的患者（OA组），20例来自因高能髋部骨折接受髋关节置换术的患者（对照组）。肌肉活检样本用4%多聚甲醛固定，石蜡包埋。连续切片用于形态计量和免疫组化分析（BMP/2/4-7、肌肉生长抑制素、Smad1-5-8、Pax7和生肌调节因子）。此外，将每位患者1mm的肌肉组织包埋在环氧树脂中进行超微结构研究。
形态计量数据表明，与OA组相比，OP组萎缩纤维数量增加。与这些数据一致的是，我们发现OA组患者的肌肉组织具有较高的再生潜力，因为在OA组中检测到大量Pax7和生肌调节因子阳性的卫星细胞。此外，我们的数据显示，与OA组和对照组相比，OP组患者BMP2/4和-7的表达降低。相反，OP组患者的肌肉生长抑制素表达水平较高。OP组和OA组患者磷酸化Smad1-5-8的表达谱也不同。特别是，OP组患者磷酸化Smad1-5-8阳性细胞核数量较少。
确定参与肌肉减少症发病机制的分子途径为开发能够预防/治疗老年人肌肉损伤的药物开辟了新的前景。本文报道的结果突出了BMPs和肌肉生长抑制素信号通路在人类肌肉减少症生理发病机制中的作用，使我们能够提出人重组BMP-2/7和抗肌肉生长抑制素抗体作为治疗肌肉减少症的一种可能的治疗选择。
