Neutralizing hepatic apolipoprotein E enhances aged bone fracture healing

Area of Science:

• Bone Biology and Regenerative Medicine
• Aging and Gerontology
• Molecular Mechanisms of Disease

Background:

• Advanced age is associated with impaired bone fracture healing, but the underlying molecular mechanisms are not fully understood.
• Apolipoprotein E (ApoE) levels increase with age and have been implicated in this age-related decline in bone healing.

Purpose of the Study:

• To elucidate the mechanism by which ApoE affects bone fracture healing in aged individuals.
• To identify potential therapeutic targets for enhancing bone regeneration in the elderly.

Main Methods:

• Utilized knockout mice (ΔApoE) to reduce hepatic ApoE expression and assessed fracture healing.
• Investigated ApoE's effect on bone marrow stromal cells (BMSCs) differentiation using cell culture, RNA-seq, Western blot, immunofluorescence, and RT-PCR.
• Identified the ApoE receptor (Lrp4) and its role in the Wnt/β-catenin pathway.
• Administered an ApoE-neutralizing antibody (NAb) to aged mice post-fracture.

Main Results:

• Aged mice with reduced ApoE levels (ΔApoE) exhibited significantly improved fracture healing.
• ApoE inhibited osteoblast differentiation in vitro by targeting the Wnt/β-catenin pathway, an effect dependent on Lrp4 expression.
• This ApoE-Lrp4-Wnt/β-catenin mechanism was validated in human osteoblast differentiation.
• Treatment with an ApoE-neutralizing antibody increased bone deposition in fracture calluses of aged mice by 35%.

Conclusions:

• Apolipoprotein E (ApoE) plays a critical role in age-related impairment of bone fracture healing.
• The liver-bone cross-talk involving ApoE, its receptor Lrp4, and the Wnt/β-catenin pathway is a key mechanism.
• An ApoE-neutralizing antibody represents a promising, noninvasive therapeutic strategy for improving bone regeneration in aged populations.