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

Authors: CAVINESS, PERRY - Arkansas Children'S Nutrition Research Center (ACNC); LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC); BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC); CHEN, JENNIFER - University Of Arkansas; RANDOLPH, CHROSTOPHER - Arkansas Children'S Nutrition Research Center (ACNC); ZABELETA, J - Louisiana State University; ZHAN, FENGHUANG - University Of Arkansas; CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/12/2024
Publication Date: 2/15/2024
Citation: Caviness, P.C., Lazarenko, O.P., Blackburn, M.L., Chen, J.F., Randolph, C.E., Zabeleta, J., Zhan, F., Chen, J. 2024. Phenolic acids prevent sex-steroid deficiency-induced bone loss and bone marrow adipogenesis in mice. Journal of Nutritional Biochemistry. 127. Article 109601. https://doi.org/10.1016/j.jnutbio.2024.109601.
DOI: https://doi.org/10.1016/j.jnutbio.2024.109601

Interpretive Summary: Problem Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) can promote bone formation and suppress bone resorption making both molecule potential new therapeutic options for treating and preventing bone resorptions disorders such as osteoporosis. The mechanisms by which HA and 3-3-PPA are bone protecting are currently unknown and an understanding of the mechanism would assist in developing both molecules as potential new anti-bone resorption agents. Accomplishment In this report we found that both HA and 3-3-PPA had bone protecting ability comparable to the commonly prescribed drug zoledronic acid (ZA) in an estrogen deficient (menopausal) mouse model. Both HA and 3-3-PPA preventing fat tissue in bone marrow by suppressing expression of key enzymes lipoprotein lipase (Lpl) and peroxisome proliferator activated receptor gamma (PPAR') as well as the association between Lpl and PPAR'. Evidence from this report shows that ZA protects against bone resorption by killing osteoclasts but it may also kill other non-bone resorbing cells. Contribution Data from this report suggest that phenolics acids such as HA or 3-3-PPA may be safer alternative anti-bone resorption agents than ZA for treatment of bone resorption disorders.

Technical Abstract: Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA), can be produced from microbiome digestion of polyphenols. Previously it was found that HA and 3-3-PPA facilitate bone formation and suppress bone resorption. However, the mechanism of action by which HA and 3-3-PPA protect bone from degeneration is currently 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 treatments were shown to significantly decrease bone marrow adipocyte-like cell formation and inhibited gene expression of key adipogenesis regulator peroxisome proliferator activated receptor gamma (PPAR') and lipoprotein lipase (Lpl) in bone from OVX mice. In addition, ChIP experiments showed that the association between PPAR' and Lpl promoter region in preadipocyte-like cells was significantly suppressed following HA or 3-3-PPA treatment. Contrasting HA and 3-3-PPA, ZA significantly increased TRAP activity in the area close to growth plate and significantly suppressed bone cell proliferation. These data suggest that phenolics acids such as HA or 3-3-PPA may prevent bone degeneration after OVX through suppression of inflammatory milieu in the bone.