Zoledronic acid prevents pagetic-like lesions and accelerated bone loss in the p62P394L mouse model of Paget's disease

Disease Models & Mechanisms
Anna DaroszewskaRobert J van 't Hof

Abstract

Paget's disease of bone (PDB) is an age-related metabolic bone disorder, characterised by focally increased and disorganised bone remodelling initiated by abnormal and hyperactive osteoclasts. The germline P392L mutation of SQSTM1 (encoding p62) is a strong genetic risk factor for PDB in humans, and the equivalent mutation in mice (P394L) causes a PDB-like disorder. However, it is unclear why pagetic lesions become more common with age. Here, we assessed the effect of the p62 P394L mutation on osteoclastogenesis and bone morphometry in relation to ageing, the natural history of lesion progression in p62P394L mice and the effect of zoledronic acid (ZA) on lesion development. p62P394L+/+ osteoclast precursors had increased sensitivity to RANKL (also known as TNFSF11) compared with wild-type (WT) cells, and the sensitivity further increased in both genotypes with ageing. Osteoclastogenesis from 12-month-old p62P394L+/+ mice was twofold greater than that from 3-month-old p62P394L+/+ mice (P<0.001) and three-fold greater than that from age-matched WT littermates. The p62P394L+/+ mice lost 33% more trabecular bone volume in the long bones by 12 months compared with WT mice (P<0.01), and developed pagetic-like lesions in the long bone...Continue Reading

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Citations

May 1, 2019·Proceedings of the National Academy of Sciences of the United States of America·Barry ShawRobert Layfield
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Methods Mentioned

BETA
transgenic
Fluorescent
Fluorescent microscopy
X-ray

Clinical Trials Mentioned

ISRCTN11616770

Software Mentioned

CTAn
Skyscan dataviewer
Skyscan NRecon
Skyscan CTAn

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