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

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 bones which progressed with ageing. ZA prevented the development of pagetic-like lesions, and increased trabecular bone volume tenfold compared with vehicle by 12 months of age (P<0.01). This demonstrates that ageing has a pro-osteoclastogenic effect, which is further enhanced by the p62 P394L mutation, providing an explanation for the increased penetrance of bone lesions with age in this model. Lesions are prevented by ZA, providing a rationale for early intervention in humans.

Insertion Mutation in Tnfrsf11a Causes a Paget's Disease–Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice

“…Results from 12-month-old mice showed lytic lesions at the proximal tibia and distal femur close to the growth plate and at both lower femoral condyles in Tnfrsf11a 75dup27/mice ( Figure 4A). These lesions were similar to those previously reported in other mouse models of Paget's disease (12)(13)(14) . Most 12-month old heterozygous animals (7 out of 8) showed lesions similar to those shown in Figure 4A but by 15 months all (10 out of 10) Tnfrsf11a 75dup27/mice had developed lesions.…”

Molecular insights into an ancient form of Paget’s disease of bone

“…Mice with a proline-to-leucine mutation at codon 394 of sqstm1 , equivalent to the most common P392L mutation in humans, develop an age-associated bone disorder with similarity to PDB (13). This bone disorder can be prevented by infusion with zoledronic acid, which is the first-line treatment for PDB in humans (14). SQSTM1 is also relevant to disease etiology in PDB patients without mutations.…”

Paget’s Disease of Long Bones: Microstructural Analyses of Historical Bone Samples

“…Finally, the current investigation could be useful and support several studies related to the bone microstructure analyses in experimental models (i.e., transgenic animal models) of Paget's disease [51,52].…”