Mesenchymal stem cells for treating osteogenesis imperfecta: directly differentiating into functional cells or functioning via paracrine mechanism?

doi:10.3969/j.issn.2095-4344.0672

Abstract

Abstract:

BACKGROUND: Some limitations involving drug therapies and surgical treatment exist in the traditional treatment of osteogenesis imperfecta. In recent years, a growing number of scientists attempt to treat osteogenesis imperfecta by mesenchymal stem cells transplantation.
OBJECTIVE: To summarize the mesenchymal stem cell treatment of osteogenesis imperfecta to guide relevant animal experiments, thereby promoting its clinical application.
METHODS: A computer-based online search of PubMed between January 2000 and June 2018 was performed to search related articles with the keywords of “osteogenesis imperfecta, stem cells, mesenchymal stem cells, stem cells therapy, stem cells transplantation” in English. Literatures regarding mesenchymal stem cells for treatment of osteogenesis imperfecta were selected; in the same field, the articles published lately in authoritative journals were preferred.
RESULTS AND CONCLUSION: Mesenchymal stem cells can directly differentiate into functional cells or exert paracrine effect to repair bone defects caused by osteogenesis imperfecta. The low immunogenicity and immunomodulatory capacity of mesenchymal stem cells ensure the transplantation safety in the treatment of osteogenesis imperfecta. Mesenchymal stem cells can fundamentally treat osteogenesis imperfecta, and do not produce adverse reactions that are unavoidable in the drug treatment, which have broad application prospects. Although there are currently no systematic criteria for the efficacy and safety of mesenchymal stem cells in the treatment of osteogenesis imperfecta, mesenchymal stem cell transplantation can circumvent the limitations of conventional drugs and surgical treatment. Further studies are expected to improve the treatment of osteogenesis imperfecta using mesenchymal stem cells and promote its clinical applications, as cell transplantation indeed benefits the patients.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Osteogenesis Imperfecta, Mesenchymal Stem Cell Transplantation, Tissue Engineering

CLC Number:

R394.2

Wang Zi-han, Liu Yi, Ju Ming-yan, Li Guang. Mesenchymal stem cells for treating osteogenesis imperfecta: directly differentiating into functional cells or functioning via paracrine mechanism?[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(33): 5373-5378.

Figures/Tables 2

正常骨的生长发育，需要成骨细胞的骨形成作用和破骨细胞的骨吸收作用共同维持，成骨与破骨的平衡是维持正常骨量的关键。成骨细胞是骨形成的主要功能细胞，负责骨基质的合成、分泌和矿化[2]。Ⅰ型胶原是骨基质中含量最多(约占90%)的有机成分，由2条COL1A1基因编码的α1链和1条COL1A2基因编码的α2链构成，α1链和α2链中含有甘氨酸(glycine，Gly)三联体的Gly-X-Y重复序列(X和Y多为脯氨酸和羟脯氨酸)，形成稳定的三股螺旋结构[8]。胶原分子之间通过共价键横向交联，构成钙和磷等矿物质沉积的矿化骨架[8]。COL1A1/COL1A2基因中任何一个位点发生突变都有可能使成骨细胞合成胶原的结构或量发生异常改变，进而引起矿化异常，导致成骨不全发生。目前报道的COL1A1/COL1A2基因突变包括无义突变、错义突变、移码突变、剪接突变等类型，其中无义突变、移码突变、剪接突变主要使胶原数量减少，其患者临床症状较轻，通常为Ⅰ型；错义突变主要导致三联体中甘氨酸被丝氨酸为主的其他氨基酸替代，引起Ⅰ型胶原蛋白三螺旋区域空间构象改变，其患者临床表型较重，主要为Ⅱ-Ⅳ型(Ⅱ型常于宫内死亡或在出生后短期内死亡，临床不常见)[11]。 2.2 成骨不全的传统治疗方法目前，临床上针对成骨不全主要有药物治疗和外科手术治疗等方法。成骨不全的药物治疗中，双膦酸盐类是目前临床治疗成骨不全最有效的药物[2]，可以提高骨密度、降低骨折发生风险、减轻骨痛、增强肌力、改善生活质量等[12-15]，但不同种类双膦酸盐的用药剂量不同，对成骨不全患者的疗效也不同，仍有待进一步研究[14]，且长期使用会出现颌骨坏死、食管癌、严重肌肉骨骼痛和肾功能衰竭等严重不良反应[15]。除双膦酸盐类之外，还有一些药物研究主要以抑制破骨和调节成骨合成代谢为主，包括生长激素、甲状旁腺激素、骨硬化蛋白抗体等。生长激素可直接作用于成骨细胞[16]，促进Ⅰ型胶原的合成和长骨的生长发育[17]，但同时增加骨转换率，使成骨不全患者存在畸形加重的风险[18]。甲状旁腺激素可调节哺乳动物钙磷代谢[19]，激活休眠的骨内膜细胞并促进其分化为成骨细胞，使成骨细胞的数目显著增加，进而增加骨形成率，提高患者骨量和骨密度[20]，但能否作为成骨不全的一线用药仍需进一步研究。骨硬化蛋白抗体可以靶向抑制骨硬化蛋白[21]，促进骨形成，提高骨量[22]，被广泛用于骨质疏松症的研究，治疗胶原蛋白翻译后修饰缺陷引起的成骨不全效果显著[23]，但仍处于动物实验阶段[24]，临床治疗成骨不全的研究未见报道。成骨不全的外科手术治疗主要集中在长骨畸形及反复骨折、脊柱侧凸和听力缺失的矫正与治疗等。针对长骨畸形、移位和不稳定性骨折，除常规的钢板固定和骨切开术外，还可通过微创手术在长骨骨髓腔内放置可伸缩髓内钉，不仅无需进行关节切除就可稳定严重骨折，而且在矫正治疗中断后仍能提供持续的内部支撑[3]。尽管可伸缩髓内钉可降低移位率，但手术操作难度大，术后并发症较多，易增加成骨不全患者再骨折风险[25]。脊柱侧凸是成骨不全的常见并发症之一，常引起疼痛和活动障碍，严重时亦可危及生命。当成骨不全患者脊柱稳定且Cobb角> 50°时，可采用halo式支架以防止侧凸的持续加重[26]，但其应用可能会导致脊柱韧带松弛，使曲线矫正的效果逐渐丧失[27]。成骨不全也常伴随听力缺失的发生，在成骨不全患者听力缺失初期可使用助听器进行治疗，但随着病情的不断加重，患者则需进行镫骨切除术治疗[28]。 2.3 MSCs治疗成骨不全的可行性(图1)"

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