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Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.

ABSTRACT: Marrow adipocytes and osteoblasts differentiate from common mesenchymal progenitors in a mutually exclusive manner, and diversion of these progenitors toward adipocytes in old age has been proposed to account for the decline in osteoblasts and the development of involutional osteoporosis. This idea has been supported by evidence that thiazolidinedione (TZD)-induced activation of PPAR?, the transcription factor required for adipocyte differentiation, increases marrow fat and causes bone loss. We functionally tested this hypothesis using C57BL/6J mice with conditional deletion of PPAR? from early mesenchymal progenitors targeted by the Prx1-Cre transgene. Using a longitudinal littermate-controlled study design, we observed that PPAR? is indispensable for TZD-induced increase in marrow adipocytes in 6-month-old male mice, and age-associated increase in marrow adipocytes in 22-month-old female mice. In contrast, PPAR? is dispensable for the loss of cortical and trabecular bone caused by TZD or old age. Instead, PPAR? restrains age-dependent development of cortical porosity. These findings do not support the long-standing hypothesis that increased marrow adipocyte differentiation contributes to bone loss in old age but reveal a novel role of mesenchymal cell PPAR? in the maintenance of cortical integrity.

SUBMITTER: Almeida M

PROVIDER: S-EPMC7681065 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.

Almeida Maria M Kim Ha-Neui HN Han Li L Zhou Daohong D Thostenson Jeff J Porter Ryan M RM Ambrogini Elena E Manolagas Stavros C SC Jilka Robert L RL

Aging cell 20201013 11

Marrow adipocytes and osteoblasts differentiate from common mesenchymal progenitors in a mutually exclusive manner, and diversion of these progenitors toward adipocytes in old age has been proposed to account for the decline in osteoblasts and the development of involutional osteoporosis. This idea has been supported by evidence that thiazolidinedione (TZD)-induced activation of PPARγ, the transcription factor required for adipocyte differentiation, increases marrow fat and causes bone loss. We ...[more]

PMID: 33048436

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Project description:Cell-extracellular matrix (ECM) interactions play major roles in controlling progenitor cell fate and differentiation. The receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), is an important mediator of interactions between cells and fibrillar collagens. DDR2 signals through both ERK1/2 and p38 MAP kinase, which stimulate osteoblast differentiation and bone formation. Here we show that DDR2 is critical for skeletal development and differentiation of marrow progenitor cells to osteoblasts while suppressing marrow adipogenesis. Smallie mice (Ddr2slie/slie ), which contain a nonfunctional Ddr2 allele, have multiple skeletal defects. A progressive decrease in tibial trabecular bone volume/total volume (BV/TV) was observed when wild-type (WT), Ddr2wt/slie , and Ddr2slie/slie mice were compared. These changes were associated with reduced trabecular number (Tb.N) and trabecular thickness (Tb.Th) and increased trabecular spacing (Tb.Sp) in both males and females, but reduced cortical thickness only in Ddr2slie/slie females. Bone changes were attributed to decreased bone formation rather than increased osteoclast activity. Significantly, marrow fat and adipocyte-specific mRNA expression were significantly elevated in Ddr2slie/slie animals. Additional skeletal defects include widened calvarial sutures and reduced vertebral trabecular bone. To examine the role of DDR2 signaling in cell differentiation, bone marrow stromal cells (BMSCs) were grown under osteogenic and adipogenic conditions. Ddr2slie/slie cells exhibited defective osteoblast differentiation and accelerated adipogenesis. Changes in differentiation were related to activity of runt-related transcription factor 2 (RUNX2) and PPARγ, transcription factors that are both controlled by MAPK-dependent phosphorylation. Specifically, the defective osteoblast differentiation in calvarial cells from Ddr2slie/slie mice was associated with reduced ERK/MAP kinase and RUNX2-S319 phosphorylation and could be rescued with a constitutively active phosphomimetic RUNX2 mutant. Also, DDR2 was shown to increase RUNX2-S319 phosphorylation and transcriptional activity while also increasing PPARγ-S112 phosphorylation, but reducing its activity. DDR2 is, therefore, important for maintenance of osteoblast activity and suppression of marrow adipogenesis in vivo and these actions are related to changes in MAPK-dependent RUNX2 and PPARγ phosphorylation. © 2016 American Society for Bone and Mineral Research.

Dataset Information

Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.

Publications

Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.

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