Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
J Bone Miner Res. 2021 Jul;36(7):1376-1386. doi: 10.1002/jbmr.4288. Epub 2021 May 6.
Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a ) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
早发性家族性 Pagets 骨病（EoPDB）、家族性扩张性溶骨症和扩张性骨骼高磷酸酶症是由 TNFRSF11A 基因外显子 1 中的插入突变引起的相关疾病，该基因编码核因子 κB 受体激活物（RANK）蛋白。为了了解这些疾病的发病机制，我们构建了一个携带导致 EoPDB 的 75dup27 突变的小鼠模型。该突变杂合子（Tnfrsf11a ）小鼠随年龄增长在四肢出现 PDB 样病变伴局灶性溶骨性病变。用唑来膦酸治疗这些小鼠可完全预防病变发生。体外研究表明，RANKL 诱导的破骨细胞形成和信号在 Tnfrsf11a 动物的骨髓细胞中受损，但破骨细胞存活增加而不依赖于 RANKL 刺激。令人惊讶的是，Tnfrsf11a 纯合子出生时即发生骨硬化症，完全缺乏破骨细胞。这些小鼠的骨髓细胞无法对 RANKL 和巨噬细胞集落刺激因子（M-CSF）刺激作出反应而形成破骨细胞。这项有趣的研究表明，在杂合子形式中，75dup27 突变导致体内出现类似于人类疾病的局灶性溶骨性病变，并独立于 RANKL 信号延长破骨细胞存活。然而，在纯合子形式中，由于破骨细胞形成失败和对 RANKL 刺激不敏感，该突变导致骨硬化症。© 2021 作者。由 Wiley 期刊出版公司代表美国骨骼矿物质研究协会（ASBMR）出版的《骨与矿物研究杂志》。
