Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications

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Abstract

The increase in marrow adipogenesis associated with osteoporosis and age-related osteopenia is well known clinically. However, we are only now beginning to understand the mechanisms that control the differentiation of mesenchymal stem cells to either osteoblasts or adipocytes. Recent work with gene silencing and overexpression has provided insight into critical pathways that determine the fate of these multipotential cells. One of these pathways — that of the nuclear hormone receptor peroxisome proliferator activated receptor-γ — when activated, promotes adipogenesis and inhibits osteogenesis. This in vitro mechanism of action has been confirmed in vivo using ligands to this receptor. Discovery of this and other targets and pathways, such as Wnt signaling, notch/delta/jagged ligands and receptors, and RhoA gene expression, provides new insights into mesenchymal stem cell differentiation. These pathways provide exciting future pharmacological targets with which to enhance bone formation and therefore reduce the risk of fracture.

Introduction

As individuals live longer lives, they have a greater risk of developing osteoporosis. Disorders relating to bone loss are now a major cause of morbidity and mortality in the industrialized world, and the cost of treating these medical illnesses continues to grow. This review highlights recent advances concerning the basic mechanisms controlling osteoblast and adipocyte differentiation. This information could provide insights that result in the identification of new lead compounds for therapeutic intervention.

Section snippets

Potential therapeutic pathways

The decrease in bone volume associated with osteoporosis and age-related osteopenia is accompanied by an increase in marrow adipose tissue 1., 2.. Indeed, an increase in marrow adipocytes is observed in all conditions that lead to bone loss, such as ovariectomy [3], immobilization [4] or treatment with glucocorticoids [5]. Marrow adipocytes share a common mesenchymal stem cell (MSC) with bone-forming osteoblasts. Therefore, the balance between bone formation and marrow adipogenesis might

Potential confounding issues

Tissue and cell specificity remain critical features that all pharmacological interventions need to address (Box 1). Each of these metabolic pathways is essential to the differentiation and development of multiple cell lineages. Therefore, one challenge is to design drugs that specifically act on bone and bone marrow, without influencing tissue development elsewhere in the patient. If a compound promotes osteogenesis and inhibits adipogenesis within the bone marrow microenvironment, and also

Conclusions

Osteoporosis continues to grow as a medical issue throughout the world. The balance between adipose and bone formation within the bone marrow microenvironment presents a target for pharmacological intervention in this disorder. This brief review has highlighted some of the metabolic pathways regulating stromal cell differentiation along these lineages. This is by no means a complete list; new technologies are uncovering alternative candidates for drug development efforts. The next few years

Update

Recent work by Akune et al. [40••] has shown that PPARγ deficiency promotes osteoblastogenesis. They observed that embryonic stem cells from PPARγ-deficient mice spontaneously underwent osteogenesis but failed to undergo adipogenesis. Although mice displaying the homozygous PPARγ−/− haplotype were embryonic lethal, their heterozygous PPARγ−/+ littermates survived. PPARγ−/+ mice exhibited increased trabecular bone volume when compared with their wild-type littermates. Moreover, in vitro studies

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The authors wish to thank Moustapha Kassem and Beata Lecka-Czernik for their comments and suggestions.

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