Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, via Vetoio-Coppito 2, 67100 L'Aquila, Italy.
Department of Medicine, Indiana University, 1120 W. Michigan St., Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University, 1120 W. Michigan St., Indianapolis, IN 46202, USA.
Bone. 2017 Sep;102:50-59. doi: 10.1016/j.bone.2017.02.002. Epub 2017 Feb 4.
Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure. Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.
石骨症是一组罕见的遗传性骨病，具有共同的特征，包括破骨细胞活性降低、骨量增加和骨脆性增加。破骨细胞是一种骨吸收细胞，通过侵蚀矿化基质促进骨生长和更新。除了成骨细胞的成骨活性外，破骨细胞还允许骨骼和谐生长，并在骨吸收和形成之间保持健康平衡。石骨症中破骨细胞的损伤阻止了骨的更新，降低了骨质量，导致非外伤性骨折。石骨症的严重程度不同，是由参与骨吸收或破骨细胞生成的各种基因突变引起的。常见的体征和症状包括骨硬化、畸形、侏儒症和骨管狭窄，包括神经孔，导致血液学和神经功能衰竭。该病为常染色体遗传，迄今为止只有一种极其罕见的形式与 X 染色体相关，且可以是隐性或显性遗传。隐性石骨症在婴儿期或儿童期通常是致命的，只有少数较轻的形式在临床上被称为中间石骨症。显性石骨症迄今为止仅与 CLCN7 基因突变相关，虽然被描述为良性形式，但它可能会严重致残，尽管不如隐性形式严重，而且很少导致预期寿命缩短。由于破骨细胞自主性缺陷引起的严重石骨症可以通过造血干细胞移植（HSCT）治疗，但由于前破骨细胞生成细胞因子 RANKL 缺乏引起的石骨症不适合该程序。同样，尚不清楚 HSCT 是否会改善常染色体显性遗传石骨症的临床症状，因为它具有很高的内在风险。因此，需要确定新的治疗方法，目前正在进行研究以测试基因和细胞疗法、小干扰 RNA 方法和新型药物治疗。
