Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications
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:
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of special interest
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of outstanding interest
Acknowledgements
The authors wish to thank Moustapha Kassem and Beata Lecka-Czernik for their comments and suggestions.
References (40)
- et al.
Histological evidence for osteopenia and increased bone turnover in ovariectomized rats
Bone
(1986) - et al.
Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis?
Bone
(2000) - et al.
The function of adipocytes in the bone marrow stroma: an update
Bone
(1996) - et al.
Notch-1 controls the expression of fatty acid-activated transcription factors and is required for adipogenesis
J Biol Chem
(1997) - et al.
Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation
Cell
(1993) - et al.
Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway
J Biol Chem
(2001) - et al.
A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait
Am J Hum Genet
(2002) - et al.
High bone density due to a mutation in LDL-receptor-related protein 5
N Engl J Med
(2002) - et al.
Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies
Clin Orthop
(1971) - et al.
Changes in trabecular bone, hematopoesis and bone marrow vessels in aplastic anaemia, primary osteoporosis and old age: a comparative histomorphometric study
Bone
(1987)
Quantitative histological data on disuse osteoporosis
Calcif Tissue Res
Fat cell changes as a mechanism of avascular necrosis in the femoral head in cortisone-treated rabbits
J Bone Joint Surg
Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells
Mol Pharmacol
Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2
J Cell Biochem
Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation
Endocrinology
Troglitazone treatment increases bone marrow adipose tissue volume but does not affect trabecular bone volume in mice
Calcif Tissue Int
Bone is a target for the antidiabetic compound rosiglitazone
Endocrinology
Regulation of bone mass in mice by the lipoxygenase gene Alox15
Science
Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells
J Bone Miner Res
The function of adipocytes in the bone marrow stroma
New Biol
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