APOE is a component of the low density lipoprotein (LDL) particles that carry cholesterol from the liver to where it is needed in the body. Lowering circulating LDL-cholesterol levels to modestly slow the progression of atherosclerosis is the primary approach taken in cardiovascular medicine; in recent years, new forms of LDL-lowering therapy such as PCSK9 inhibitors have been used to dramatically reduce LDL-cholesterol to far below normal levels with no immediately apparent prohibitively negative effects on patients.
In today’s open access paper, researchers show that elevated APOE levels are a feature of old age and negatively affect bone regeneration, likely by suppressing the creation of osteoblast cells responsible for producing bone extracellular matrix structures. A near complete elimination of APOE production in the liver (which will also have the consequence of dramatically reducing LDL-cholesterol in circulation) improves the regeneration of fractures in old mice. There is clearly still a sense of caution in making permanent changes of this nature, despite ongoing development such as Verve Therapeutics’ gene-editing PCSK9 inhibition therapy.
Neutralizing hepatic apolipoprotein E enhances aged bone fracture healing
In our previously published study, we demonstrated that circulating ApoE levels increase with age in patients and in mice and that by using liver targeted AAV to deliver siRNA for ApoE we decreased circulating ApoE levels and increased bone deposition and mechanical stability of healed tissue. However, the potential negative impact on a patient’s cardiovascular health resulting from the permanent lowering of ApoE precludes this therapeutic strategy. Therefore, in the current study we aimed to use a neutralizing antibody against ApoE which would be cleared from the body by immune cells.
In this study we identified the mechanism of action by which hepatic ApoE inhibits fracture healing and identified a translatable non-invasive therapeutic intervention to improve aged bone repair. We knocked out hepatic ApoE expression in mice – this decreased levels of circulating ApoE and increased bone deposition and tissue mineral density within the fracture callus. Using tissue culture models, we found ApoE inhibits bone marrow stem cell to osteoblast differentiation and activity by binding to the cell-surface receptor Lrp4 and inhibiting Wnt/β-catenin signaling. Moreover, the same mechanism of action was identified during ApoE-induced inhibition of human bone marrow stem cells.
Finally, aged wildtype mice underwent tibial fracture surgery and were treated with a neutralizing antibody for ApoE 3 days post-injury which decreased levels of circulating ApoE and significantly improved fracture healing.
