Blueberry Diet Derived 3‐(3‐hydroxyphenyl) Propionic Acid (PPA) Suppresses Osteoblastic Cell Senescence to Promote Bone Accretion in Mice

Abstract

A blueberry (BB) supplemented diet has been previously shown to significantly stimulate bone formation in rapidly growing male and female rodents. Phenolic acids (PAs) are metabolites derived from polyphenols found in fruits and vegetables as a result of the actions of gut bacteria, and the levels of seven individual PAs were found to be at least 10 times higher in the serum of rats fed a BB‐containing diet compared to those fed a control diet. We have characterized the effects of one such BB‐associated serum PA, 3‐(3‐hydroxyphenyl) propionic acid (PPA), on stimulating osteoblastogenesis. To better understand the mechanistic actions of PPA on bone formation, we administered four doses of PPA (0.1, 0.5, 1 and 5 mg/kg/d) to one‐month‐old female C57BL6/J mice for thirty days. We found that stimulation of osteoblast differentiation and proliferation occurred in PPA treated osteoblastic cells. Using peripheral quantitative CT scan (pQCT) and micro‐CT analyses, we demonstrated differences in bone phenotypes between control and PPA‐treated animals, i.e., bone mass was significantly higher in 1 to 5 mg/kg/d PPA‐treated animals compared to controls (p<0.05). Micro‐CT showed bone volume and trabecular number in 1 mg/kg/d treated animals were 0.14±0.007 and 4.76±0.095 versus 0.12±0.02 and 4.33±0.33 in control animals (p<0.05). The bone formation marker alkaline phosphatase in both serum and bone marrow plasma was dose‐dependently increased in PPA‐treated animals. After aspiration of bone marrow, femur bone protein and RNA were isolated for Western blot and real‐time PCR analysis of signaling transduction. We found that PPA was able to suppress bone senescence signaling as evaluated by measuring senescence‐associated beta‐galactosidase activity, PPARγ, p53 and p21 expression (p<0.05 vs control). In conclusion, blueberry‐derived PPA is capable of altering the mesenchymal stem cell differentiation program and bone cell senescence. Thus, PPA or blueberry‐rich diets merit investigation as potential dietary alternatives to drugs for degenerative bone disorders or to promote bone growth during development. Supported in part by USDA‐ARS Project 6026‐51000‐010‐05S.Support or Funding InformationSupported in part by USDA‐ARS Project 6026‐51000‐010‐05S