DMP1 Ablation in the Rabbit Results in Mineralization Defects and Abnormalities in Haversian Canal/Osteon Microarchitecture. (3rd March 2019)

• Record Type: Journal Article
• Authors: Liu, Tingjun; Wang, Jun; Xie, Xudong; Wang, Ke; Sui, Tingting; Liu, Di; Lai, Liangxue; Zhao, Hu; Li, Zhanjun; Feng, Jian Q
• Is Part Of: Journal of bone and mineral research. Volume 34:Number 6(2019)
• Page Start: 1115
• Page End: 1128
• Publication Date: 2019-03-03
• Subjects: DMP1 -- CRISPR/Cas9‐MEDIATED KNOCKOUT -- HYPOPHOSPHATEMIC RICKETS -- RABBIT -- OSTEON; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.3683
• Languages: English
• ISSNs: 0884-0431

Abstract

ABSTRACT: DMP1 (dentin matrix protein 1) is an extracellular matrix protein highly expressed in bones. Studies of Dmp1 knockout (KO) mice led to the discovery of a rare autosomal recessive form of hypophosphatemic rickets (ARHR) caused by DMP1 mutations. However, there are limitations for using this mouse model to study ARHR, including a lack of Haversian canals and osteons (that occurs only in large mammalian bones), high levels of fibroblast growth factor 23 (FGF23), and PTH, in comparison with a moderate elevation of FGF23 and unchanged PTH in human ARHR patients. To better understand this rare disease, we deleted the DMP1 gene in rabbit using CRISPR/Cas9. This rabbit model recapitulated many features of human ARHR, such as the rachitic rosary (expansion of the anterior rib ends at the costochondral junctions), moderately increased FGF23, and normal PTH levels, as well as severe defects in bone mineralization. Unexpectedly, all DMP1 KO rabbits died by postnatal week 8. They developed a severe bone microarchitecture defect: a major increase in the central canal areas of osteons, concurrent with massive accumulation of osteoid throughout all bone matrix (a defect in mineralization), suggesting a new paradigm, where rickets is caused by a combination of a defect in bone microarchitecture and a failure in mineralization. Furthermore, a study of DMP1 KO bones found accelerated chondrogenesis, whereas ARHR has commonly been thought to be involved in reduced chondrogenesis. Our findings with newly developed DMP1 KO rabbits suggest a revised understanding of the mechanism underlying ARHR. © 2019 American Society for Bone and Mineral Research.