|DING, KEHONG - Augusta University
|ROSARIO, RAYSA - Augusta University
|SU, YUN - Augusta University
|LAWRENCE, MEGHAN - Augusta University
|HAMRICK, MARK - Augusta University
|ISALES, CARLOS - Augusta University
|SHI, XING - Augusta University
Submitted to: Journal of Gerontology Biological Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/10/2020
Publication Date: 2/15/2020
Citation: Cao, J.J., Ding, K., Rosario, R., Su, Y., Lawrence, M., Hamrick, M., Isales, C., Shi, X. 2020. Deletion of PPARy in mesenchymal lineage cells protects against aging-induced cortical but not trabecular bone loss in mice. Journal of Gerontology Biological Science. https://doi.org/10.1093/gerona/glaa049.
Interpretive Summary: Increased chronic low-grade inflammation and bone marrow fat accumulation may contribute to age-related bone loss. Studies show that a protein called peroxisome proliferator-activated receptor gamma (PPAR') is involved in fat cell differentiation and plays an important role in bone metabolism with aging. In the current study, we investigated how PPAR' affects bone marrow stem cell differentiation, bone structure, and inflammation in mice. We used an animal model in which PPAR' gene was specifically deleted from bone stem cells. We found that old mice lacking the PPAR' gene had less fat mass and increased bone thickness but similar compared with control mice at the same age. Deletion of PPAR' gene from bone marrow stem cells decreased serum concentrations of signaling molecules secreted by fat cells and reduced expression levels of inflammation-related genes in bone marrow cells. Our results demonstrate that PPAR' may play an important role in age-related bone loss.
Technical Abstract: Bone loss in aging is linked with chronic low-grade inflammation and the accumulation of marrow fat in animals and humans. Peroxisome proliferator-activated receptor gamma (PPARy), an adipogenic regulator, plays key roles in these biological processes. However, studies of the roles of PPAR' in age-related bone loss and inflammation are lacking. We hypothesized that deletion of PPAR' in bone marrow mesenchymal lineage cells would reduce bone loss with aging, potentially through a reduction in fat-generated inflammatory responses and an increase in osteoblastic activity. In the present study, we show that mice deficient of PPAR' in Dermo1-expressing mesenchymal lineage cells (Dermo1-Cre:PPAR'fl/fl) have reduced fat mass and increased cortical bone thickness, but that deficiency of PPAR ' had limited effect on trabecular bone with aging as demonstrated by DXA, µ-CT, and histomorphometric analyses. Conditional knockout of PPAR' reduced serum concentrations of adipokines including adiponectin, resistin and leptin and reduced marrow stromal cell expression levels of inflammation-related genes. Inflammation genes involved in the regulation of interferons (IFNs) and IFN-stimulated genes were reduced the most. These results demonstrate that disruption of the master adipogenic regulator, PPAR', has a certain protective effect on aging-induced bone loss, suggesting that regulation of adipose tissue and its function, rather than direct regulation of mesenchymal stem cell osteogenic commitment, is a key mechanism for PPAR' to regulate bone homeostasis during aging process.