Location: Arkansas Children's Nutrition CenterTitle: 3-(3-hydroxyphenyl)-Propionic Acid (PPA) suppresses osteoblastic cell senescence to promote bone accretion in mice
|CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC)|
|WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC)|
|ALUND, ALEXANDER - Arkansas Children'S Nutrition Research Center (ACNC)|
|BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)|
|SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)|
|LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: JBMR Plus
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2019
Publication Date: 5/8/2019
Citation: Chen, J., Wankhade, U.D., Alund, A.W., Blackburn, M.L., Shankar, K., Lazarenko, O.P. 2019. 3-(3-hydroxyphenyl)-Propionic Acid (PPA) suppresses osteoblastic cell senescence to promote bone accretion in mice. JBMR Plus. https://doi.org/10.1002/jbm4.10201.
Interpretive Summary: Optimal bone growth during childhood helps prevent later-life risk for osteoporosis. In addition to adequate intake of nutrients such as calcium and Vitamin D, foods rich in specific bioactives may also promote bone development. For instance, supplementation of a 10% blueberry (BB) containing diet significantly stimulated bone growth in young male and female rats. It is known that gut bacteria are able to metabolize components of fruits and vegetables to produce factors such as polyphenols and thereafter phenolic acids (PAs). We previously found that concentrations of PAs in rat blood were significantly higher after a BB-containing diet. This supports the idea that increased concentration of PAs in rat blood may be one of reasons for why rats eating BB had increased bone mass. To test this concept, we treated bone-forming cells (osteoblasts) with 3-(3-hydroxyphenyl)-propionic acid (PPA), one of the PAs in rat blood after BB diet. There were significantly more osteoblast numbers in the PPA-treated cell culture plates compared to no PPA. We therefore next performed a study in mice; PPA solution was administered daily for 30 days. Mice with PPA solution injection had stronger bone compared to those mice with saline solution injection. PPA particularly inhibited cell aging pathways. These studies highlight that PPA--a compound that can be derived from certain fruits such as blueberries--is capable of altering the bone cell differentiation program to drive net bone development. These properties may explain, in part, the bone-promoting aspects of dietary blueberries and provides a new mechanism by which bone cells are regulated by diet in the body.
Technical Abstract: Phenolic acids (PAs) are metabolites derived from polyphenolic compounds found in fruits and vegetables resulting from the actions of gut bacteria. Previously, we reported that the levels of seven individual PAs were found to be at least 10 times higher in the serum of rats fed a blueberry (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 senescence signaling and promotion of mesenchymal stem cell differentiation toward osteoblasts, while suppressing adipogenesis in the stem cells. To better understand the mechanistic actions of PPA on bone formation in vivo, we administered four doses of PPA (0.1, 0.5, 1 and 5 mg/kg/d; daily i.p.) to one-month-old female C57BL6/J mice for 30 days. We did not observe significant effects of PPA on cortical bone, however, there were significantly higher bone volume and trabecular thickness in 0.1, 0.5 and 1 mg/kg/d PPA-treated groups compared to controls. These outcomes were reflected in changes of bone formation markers in serum and bone marrow plasma. PPA treatment reduced senescence signaling as evaluated by senescence-associated B-galactosidase activity, PPAR', p53 and p21 expression in bone. In conclusion, PPA is capable of altering the mesenchymal stem cell differentiation program and bone cell senescence. This raises the possibility that BB-rich diets promote bone growth through increasing systemic PAs, a question that merits additional investigation.