OrthoRaMS – Gurpreet Baht, PhD

“ApoE: A new target to improve aged bone fracture healing”

Presented by Gurpreet S. Baht, PhD (Duke University)

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.

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