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Lowering circulating apolipoprotein E levels improves aged bone fracture healing
Rong Huang, … , Phillip J. White, Gurpreet S. Baht
Rong Huang, … , Phillip J. White, Gurpreet S. Baht
Published September 19, 2019
Citation Information: JCI Insight. 2019;4(18):e129144. https://doi.org/10.1172/jci.insight.129144.
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Research Article Bone biology

Lowering circulating apolipoprotein E levels improves aged bone fracture healing

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Abstract

Age is a well-established risk factor for impaired bone fracture healing. Here, we identify a role for apolipoprotein E (ApoE) in age-associated impairment of bone fracture healing and osteoblast differentiation, and we investigate the mechanism by which ApoE alters these processes. We identified that, in both humans and mice, circulating ApoE levels increase with age. We assessed bone healing in WT and ApoE–/– mice after performing tibial fracture surgery: bone deposition was higher within fracture calluses from ApoE–/– mice. In vitro recombinant ApoE (rApoE) treatment of differentiating osteoblasts decreased cellular differentiation and matrix mineralization. Moreover, this rApoE treatment decreased osteoblast glycolytic activity while increasing lipid uptake and fatty acid oxidation. Using parabiosis models, we determined that circulating ApoE plays a strong inhibitory role in bone repair. Using an adeno-associated virus–based siRNA system, we decreased circulating ApoE levels in 24-month-old mice and demonstrated that, as a result, fracture calluses from these aged mice displayed enhanced bone deposition and mechanical strength. Our results demonstrate that circulating ApoE as an aging factor inhibits bone fracture healing by altering osteoblast metabolism, thereby identifying ApoE as a new therapeutic target for improving bone repair in the elderly.

Authors

Rong Huang, Xiaohua Zong, Puviindran Nadesan, Janet L. Huebner, Virginia B. Kraus, James P. White, Phillip J. White, Gurpreet S. Baht

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Figure 6

Decreasing circulating ApoE levels improves bone regeneration in aged mouse models.

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Decreasing circulating ApoE levels improves bone regeneration in aged mo...
(A) Schematic diagram: 24-month-old mice were injected with AAV carrying either GFP or siRNA-ApoE. Mice underwent tibial fracture surgery and were allowed to heal for 21 days. (B) Using ELISA, 24 days after injection, circulating ApoE levels were measured within the serum of mice. (C) Using μCT, 21-day fracture calluses were assessed for (D) bone ratio within the callus and (E) tissue mineral density. Scale bar: 1 mm. Mechanical testing was performed on 28-day fracture calluses to assess (F) structural stiffness and (G) maximal force to fracture. (H and I) Alcian blue/hematoxylin/Orange G staining was performed on decalcified, paraffin-embedded sections. Areas of fibrous tissue (H, GFP, arrows) and areas of bone deposition (I, siRNA-ApoE, arrows) are depicted at indicated original magnifications. (J) Histomorphometry was used to measure the amount of bone tissue deposited within the healing fracture callus. For GFP, n = 6; for siRNA-ApoE, n = 8. Data are expressed as mean ± 95% confidence interval. *P < 0.05.

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ISSN 2379-3708

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