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Ortho RaMS – Gurpreet Baht, PhD
December 5, 2024 @ 1:00 pm - 2:00 pm
Join us for our next seminar in the OrthRaMS Seminar Series on December 5th, 2024 from 1-2 PM.
Bone fracture healing is impaired with advanced age however the underlying mechanism is unknown. Our previous work indicated circulating apolipoprotein E (ApoE) as an aging factor, increasing with age and impairing bone regeneration. Since the liver is the primary source of circulating ApoE, we deleted hepatic expression of ApoE using Albumin-Cre;ApoEfl/fl (∆ApoE) mice and investigated tibial fracture healing in aged (24-month-old) mice. ∆ApoE mice displayed 95% reduction in circulating ApoE; micro-CT and histological analysis demonstrated increased bone deposition in 21-day fracture calluses. ApoE-treatment of aged BMSCs in tissue culture models inhibited osteoblast differentiation. Subsequent RNA sequencing of these cultures indicated that the Wnt/β-catenin was the primary target of this ApoE-based inhibition. Indeed, A p o treatment had no inhibitory effect on cultures in which β-catenin levels were stabilized. We determined Lp4, whose expression was required in ApoE-based inhibition of Wnt/ß-catenin signaling and osteoblast differentiation, to be the osteoblast cell surface receptor to ApoE. Importantly, we validated this ApoE-Lrp4-Wnt/β-catenin molecular mechanism in human osteoblast differentiation. Finally, we identified an ApoE-neutralizing antibody (NAb) able to lower levels of circulating ApoE when delivered systemically. Aged, wildtype mice underwent fracture surgery and were treated with NAb 3 days post injury. Their fracture calluses contained 35% more bone tissue, evidencing improved aged fracture healing. Our work here identifies novel cross-organ communication, liver-to-bone cross-talk via hepatic ApoE expression. Using this information, we have developed a noninvasive, translatable therapeutic intervention for bone regeneration and provides a translatable therapeutic intervention.
104 Manning Drive
3200 Thurston Building, Dickson Conference Room
Chapel Hill, North Carolina 27599
United States
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