Regulation of bone and cartilage metabolism by nucleotide pyrophosphatase (NPPS) -skeletal analysis of ttw mice and its contribution to the human npps gene SNPs -

基于衰老与骨髓中成骨细胞的减少和脂肪细胞的增加相关，以及成骨细胞和脂肪细胞具有共同的祖细胞，本研究从反向和正向遗传学方法探讨了脂肪细胞分化的关键调节因子--过氧化物酶体增殖物激活受体γ（PPARγ）在骨代谢中的作用。纯合的PPARγ缺陷胚胎干细胞不能分化成脂肪细胞，但能自发分化成成骨细胞，这些细胞通过重新导入PPARγ基因得以恢复。杂合子PPARγ缺陷小鼠。表现出高骨量，成骨细胞生成增加，但成骨细胞和破骨细胞功能正常，这种作用不是由胰岛素或瘦素介导的。随着年龄的增长，PPARγ单倍不足的成骨作用变得明显，但卵巢切除术没有改变。经证实，PPARγ单倍不足可增强骨髓细胞培养中的成骨细胞生成，但不影响分化的成骨细胞或破骨细胞系细胞的培养。本研究证明了体内骨代谢的PPARγ依赖性调节，因为PPARγ不足通过刺激骨髓祖细胞的成骨细胞生成来增加骨量。然而，我们的初步研究未能揭示RXR的合成拮抗剂在几种培养系统中与PPARγ-形成异二聚体的成骨作用。此外，人类基因组分析未显示绝经后妇女中PPARγ基因的SNP与骨密度之间存在显著关联。PPARγ可能参与年龄相关性骨质疏松症的病理生理学，并将其应用于这些疾病的新治疗将是下一步的任务。

Based on the facts that ageing is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow, and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ, a key regulator of adipocyte differentiation, in bone metabolism from the reverse and forward genetic approaches. Homozygous PPARγ-deficient embryonic stem cells failed to differentiate into adipocytes but spontaneously differentiated into osteoblasts, and these were restored by the PPARγ gene reintroduction. Heterozygous PPARγ-deficient mice. exhibited high bone mass with increased osteoblastogenesis but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ haploinsufficiency became prominent with ageing, but was not changed with ovariectomy. The PPARγ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture, but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ-dependent regulation of bone metabolism in vivo, in that PPARγ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors. However, our preliminary studies failed to reveal the osteogenic action of a synthetic antagonist of RXR that forms the hererodimer with PPARγ-in several culture systems. In addition, human genomic analyses did not show the significant association between the SNPs of the PPARγ gene and bone density in postmenopausal women. Possible involvement of PPARγ in the pathophysiology of age-realted osteoporosis and its application to the novel treatment of these diseases will be next tasks to be done.