Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing.
Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing.
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DOI：
10.1016/j.bone.2015.07.035
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发表时间：
2015-12
期刊：
影响因子：
4.1
通讯作者：
Pitsillides AA
中科院分区：
文献类型：
--
作者：
Javaheri B;Carriero A;Staines KA;Chang YM;Houston DA;Oldknow KJ;Millan JL;Kazeruni BN;Salmon P;Shefelbine S;Farquharson C;Pitsillides AA
PHOSPHO 1是参与启动骨基质矿化的主要蛋白质之一。最近的研究发现，Phospho 1基因敲除小鼠（Phospho 1-R74 X）表现出多种骨骼异常，包括自发性骨折、长骨弯曲、骨软化和脊柱侧凸。然而，这些分析仅限于年轻小鼠，并且仍不清楚PHOSPHO 1的作用是否在骨转换有限的成熟小鼠骨骼中是保守的。在这项研究中，我们使用离体计算机断层扫描来检查Phospho 1缺失对不同年龄（5、7、16和34周龄）小鼠胫骨结构的影响，以确定其作用在骨骼生长和成熟过程中是否保守。据报道，基质矿化也会影响终末成骨细胞分化为骨细胞，我们还探讨了磷酸化1基因敲除小鼠中矿化不足的骨骼是否表现出修饰的骨细胞腔隙和血管孔隙。我们的数据表明，磷酸1缺乏症产生年龄相关的骨小梁结构和受损的皮质微结构的缺陷，伴随着骨细胞形状的显着改变，骨细胞陷窝和血管数量显着增加的孔隙率更大。我们的体外研究检查了来源于Phospho 1 KO和野生型小鼠的成骨细胞的行为，揭示了PHOSPHO 1缺陷细胞中基质矿化水平降低和骨细胞生成程序改变。总之，我们的数据表明，磷酸酶1的缺乏对骨结构产生了短暂的改变，并取决于年龄，但对腔隙和血管孔隙度产生了一致的改变。这可能是由于PHOSPHO 1对骨细胞分化的抑制作用导致骨结构中这些年龄相关的变化。值得注意的是，在Phospho 1 KO小鼠的低矿化骨中，骨细胞分化明显加速，这表明骨细胞发生和生物矿化之间的相互作用是不耦合的。需要进一步的研究来剖析PHOSPHO 1对骨骼衰老的调节作用的分子过程。我们的数据表明，PHOSPHO 1缺乏对骨结构的改变是短暂的，并取决于年龄。磷酸1缺乏导致骨细胞陷窝和血管孔隙增加。磷酸盐1驱动的矿化与骨细胞分化无关。
PHOSPHO1 is one of principal proteins involved in initiating bone matrix mineralisation. Recent studies have found that Phospho1 KO mice (Phospho1-R74X) display multiple skeletal abnormalities with spontaneous fractures, bowed long bones, osteomalacia and scoliosis. These analyses have however been limited to young mice and it remains unclear whether the role of PHOSPHO1 is conserved in the mature murine skeleton where bone turnover is limited. In this study, we have used ex-vivo computerised tomography to examine the effect of Phospho1 deletion on tibial bone architecture in mice at a range of ages (5, 7, 16 and 34 weeks of age) to establish whether its role is conserved during skeletal growth and maturation. Matrix mineralisation has also been reported to influence terminal osteoblast differentiation into osteocytes and we have also explored whether hypomineralised bones in Phospho1 KO mice exhibit modified osteocyte lacunar and vascular porosity. Our data reveal that Phospho1 deficiency generates age-related defects in trabecular architecture and compromised cortical microarchitecture with greater porosity accompanied by marked alterations in osteocyte shape, significant increases in osteocytic lacuna and vessel number. Our in vitro studies examining the behaviour of osteoblast derived from Phospho1 KO and wild-type mice reveal reduced levels of matrix mineralisation and modified osteocytogenic programming in cells deficient in PHOSPHO1. Together our data suggest that deficiency in PHOSPHO1 exerts modifications in bone architecture that are transient and depend upon age, yet produces consistent modification in lacunar and vascular porosity. It is possible that the inhibitory role of PHOSPHO1 on osteocyte differentiation leads to these age-related changes in bone architecture. It is also intriguing to note that this apparent acceleration in osteocyte differentiation evident in the hypomineralised bones of Phospho1 KO mice suggests an uncoupling of the interplay between osteocytogenesis and biomineralisation. Further studies are required to dissect the molecular processes underlying the regulatory influences exerted by PHOSPHO1 on the skeleton with ageing. Our data suggest that PHOSPHO1 deficiency exerts modifications in bone architecture that are transient and depend upon age. Phospho1 deficiency leads to increased osteocytic lacunar and vascular porosity. Phospho1 driven mineralisation is not coupled with osteocyte differentiation.