Phenolic acids prevent sex-steroid deficiency-induced bone loss and bone marrow adipogenesis in mice

Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA), are present in the human body throughout life from microbiome digestion of polyphenols. Previous studies showed significant effects of HA and 3-3-PPA on facilitating bone development, however, if these phytochemicals protect bone from degeneration and their mechanism of actions for doing so are unknown. In this report, we present that HA and 3-3-PPA suppression of bone resorption is able to ameliorate bone loss in an ovariectomy (OVX) osteopenic mouse model though not to the extent of Zoledronic acid (ZA). HA and 3-3-PPA treatment were shown to significantly decrease bone marrow adipocyte-like cell formation and inhibited gene expression of key adipogenesis regulator peroxisome proliferator activated receptor gamma (PPARγ) and lipoprotein lipase (Lpl) in bone from OVX mice. In addition, ChIP experiments showed that the association between PPARγ and Lpl promoter region in pre-adipocyte-like cells was significantly suppressed following HA or 3-3-PPA treatment. Contrasting HA and 3-3-PPA, ZA significantly increased TRAPase activity in the area close to growth plate and significantly suppressed bone cell proliferation. This data suggests that phenolics acids such as HA or 3-3-PPA may prevent bone degeneration after OVX through suppression of inflammatory milieu in the bone Wild-type Female C57Bl/6 were subjected to sham surgery or to ovariectomy (OVX) and 2 - 4 d after surgery they received either PBS, HA, 3-3-PPA , or ZA for 8 weeks after which mice were euthanized and the tibias collected for RNA extraction which was later used for the preparation of genomic libraries and those were sequenced to generate 1 x 75 single-end reads. Differentially expressed genes were detected in Partek Flow.