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Relationships between the Bone Expression of Alzheimer's Disease-Related Genes, Bone Remodelling Genes and Cortical Bone Structure in Neck of Femur Fracture

Author

Calcif Tissue Int. 2021 Jan 4. doi: 10.1007/s00223-020-00796-y. Online ahead of print.

Catherine J M Stapledon 1Roumen Stamenkov 2Roberto Cappai 3Jillian M Clark 1 4Alice Bourke 5L Bogdan Solomon 1 2Gerald J Atkins 6 7

Author Information

1 Centre for Orthopaedic and Trauma Research, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

2 Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, SA, Australia.

3 Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia.

4 South Australian Spinal Cord Injury Research Centre, Hampstead Rehabilitation Centre, Lightsview, SA, Australia.

5 Department of Gerontology, Royal Adelaide Hospital, Adelaide, SA, Australia.

6 Centre for Orthopaedic and Trauma Research, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia. gerald.atkins@adelaide.edu.au.

7 Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, SA, Australia. gerald.atkins@adelaide.edu.au.

Abstract

Neck of femur (NOF) fracture is a prevalent fracture type amongst the ageing and osteoporotic populations, commonly requiring total hip replacement (THR) surgery. Increased fracture risk has also been associated with Alzheimer's disease (AD) in the aged. Here, we sought to identify possible relationships between the pathologies of osteoporosis and dementia by analysing bone expression of neurotropic or dementia-related genes in patients undergoing THR surgery for NOF fracture. Femoral bone samples from 66 NOF patients were examined for expression of the neurotropic genes amyloid precursor protein (APP), APP-like protein-2 (APLP2), Beta-Secretase Cleaving Enzyme-1 (BACE1) and nerve growth factor (NGF). Relationships were examined between the expression of these and of bone regulatory genes, systemic factors and bone structural parameters ascertained from plain radiographs. We found strong relative levels of expression and positive correlations between APP, APLP2, BACE1 and NGF levels in NOF bone. Significant correlations were found between APP, APLP2, BACE1 mRNA levels and bone remodelling genes TRAP, RANKL, and the RANKL:OPG mRNA ratio, indicative of potential functional relationships at the time of fracture. Analysis of the whole cohort, as well as non-dementia (n = 53) and dementia (n = 13) subgroups, revealed structural relationships between APP and APLP2 mRNA expression and lateral femoral cortical thickness. These findings suggest that osteoporosis and AD may share common molecular pathways of disease progression, perhaps explaining the common risk factors associated with these diseases. The observation of a potential pathologic role for AD-related genes in bone may also provide alternative treatment strategies for osteoporosis and fracture prevention.