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

Abstract

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting as many as 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 y. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few noncollagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence, with Western blotting indicating p62 abnormalities, including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB-associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated domain. Ancient miRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB-associated bone tumors. Our work displays the use of proteomics to inform diagnosis of ancient diseases such as atypical PDB, which has unusual features presumably potentiated by yet-unidentified environmental or genetic factors.

Ancient microRNA profiles of 14,300-yr-old canid samples confirm taxonomic origin and provide glimpses into tissue-specific gene regulation from the Pleistocene

“…In doing so, they have detected, for instance, viral RNA genomes (Smith et al 2014;Ng et al 2014), historical plant microRNAs (Smith et al 2017) (Fordyce et al 2013). While initially only qPCR based methods were used on human remains, such as the more than 5000 years old Tyrolean iceman (Keller et al 2017), a recent aRNA sequencing study detected disease-related microRNAs from about 1000 years old human skeletons (Shaw et al 2019). While these studies represent a proof of concept for aRNA sequencing, or paleotranscriptomics, they are limited to relatively recent (~1000 years old) samples and, except for one study, restricted to plant seed-material that conveys highly favorable preservative conditions.…”

Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer

“…Mice underwent dynamic baseline scanning when tumour size had reached~200 mm 3 . We anaesthetised mice with 1-2% isoflurane.…”

“…PBC includes several These authors contributed equally: Darrell Green, Heather Eyre molecular subtypes, of which osteosarcoma is the most common. Osteosarcomas can occur in adults, but these are usually secondary to radiation exposure or Paget's disease of bone [2,3]. Major driver mutations for osteosarcoma include tumour protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) structural variants that trigger chromothripsis [4][5][6][7].…”

p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone

“…It is also associated with tumor invasion and metastasis (9). Moreover, p62 gene mutations are considered to be the main cause of Paget's disease of bone, which is a skeletal disorder characterized by excessive activation of osteoclasts, similar to GCTB (10). However, to date, the role of p62 in the mechanisms underlying the biology of GCTB has not been elucidated.…”