Schneider G B, Benis K A, Flay N W, Ireland R A, Popoff S N
Department of Cell Biology and Anatomy, Finch University of Health Sciences, Chicago Medical School, IL 60064, USA.
Bone. 1995 Jun;16(6):657-62. doi: 10.1016/8756-3282(95)00118-w.
Osteopetrosis is a heterogeneous group of bone diseases characterized by an excess accumulation of bone and a variety of immune defects. Osteopetrosis (op) and incisors absent (ia) are two nonallelic mutations in the rat which demonstrated these skeletal defects as a result of reduced bone resorption. Osteopetrotic (op) rats have severe sclerosis as a result of reduced numbers of osteoclasts which are structurally abnormal. The sclerosis in ia rats is not as severe as in op mutants; they have elevated numbers of osteoclasts, but they are also morphologically abnormal, lacking a ruffled border. Both of these mutations have defects in the inflammation-primed activation of macrophages. They demonstrate independent defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF). Because this factor may also play a role in the pathogenesis of osteoclastic dysfunction, the effects of ex vivo-generated DBP-MAF were evaluated on the skeletal system of these two mutations. Newborn ia and op rats and normal littermate controls were injected with DBP-MAF or vehicle once every 4 days from birth until 2 weeks of age, at which time bone samples were collected to evaluate a number of skeletal parameters. DBP-MAF treated op rats had an increased number of osteoclasts and the majority of them exhibited normal structure. There was also reduced bone volume in the treated op animals and an associated increased cellularity of the marrow spaces. The skeletal sclerosis was also corrected in the ia rats; the bone marrow cavity size was significantly enlarged and the majority of the osteoclasts appeared normal with extensive ruffled borders.
骨硬化症是一组异质性骨疾病，其特征是骨过度积聚和多种免疫缺陷。骨硬化症（op）和无切牙症（ia）是大鼠中的两种非等位基因突变，由于骨吸收减少而表现出这些骨骼缺陷。骨硬化症（op）大鼠由于破骨细胞数量减少且结构异常而出现严重的骨质硬化。ia大鼠的骨质硬化不如op突变体严重；它们的破骨细胞数量增加，但形态也异常，缺乏褶皱边缘。这两种突变在巨噬细胞炎症引发的激活方面都存在缺陷。它们在维生素D结合蛋白（DBP）转化为强效巨噬细胞激活因子（DBP-MAF）的级联反应中表现出独立的缺陷。由于该因子可能也在破骨细胞功能障碍的发病机制中起作用，因此评估了体外产生的DBP-MAF对这两种突变体骨骼系统的影响。新生的ia和op大鼠以及正常同窝对照从出生到2周龄每隔4天注射一次DBP-MAF或赋形剂，此时收集骨样本以评估一些骨骼参数。用DBP-MAF处理的op大鼠破骨细胞数量增加，且大多数破骨细胞结构正常。处理后的op动物骨体积也减少，骨髓腔细胞增多。ia大鼠的骨骼硬化也得到了纠正；骨髓腔大小显著增大，大多数破骨细胞看起来正常，有广泛的褶皱边缘。
