Osteoblast–adipocyte lineage plasticity in tissue development, maintenance and pathology
Osteoblasts and adipocytes share a common precursor in adult bone marrow and there is a degree of plasticity between the two cell lineages. This has important implications for the etiology of not only osteoporosis but also several other diseases involving an imbalance between osteoblasts and adipocytes. Understanding the process of differentiation of osteoblasts and adipocytes and their trans-differentiation is crucial in order to identify genes and other factors that may contribute to the pathophysiology of such diseases. Several transcriptional regulators have been shown to control osteoblast and adipocyte differentiation and function. Regulation of cell commitment occurs at the level of the progenitor cell through cross talk between complex signaling pathways and epigenetic mechanisms such as DNA methylation, chromatin remodeling, and microRNAs. Here we review the complex precursor cell microenvironment controlling osteoblastogenesis and adipogenesis during tissue development, maintenance, and pathology.
[Show abstract] [Hide abstract] ABSTRACT: Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38α in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38α regulates BM-MSC osteogenic commitment through TAK1-NF-κB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38α to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38α in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38α mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38α MAPK in skeletal development and bone remodeling.0Comments 0Citations
- "Aged BM-MSCs tend to differentiate into adipocytes at the cost of osteoblasts, which contributes to the pathogenesis of senile osteoporosis and yellowing of the bone marrow (Baldridge et al., 2010; Rachner et al., 2011 ). Reversal of the biased differentiation of aged BM-MSCs is a strategy employed for the prevention/treatment of osteoporosis (Berendsen and Olsen, 2014; Kassem and Marie, 2011; Lecka-Czernik and Stechschulte, 2014; Zaidi et al., 2012). However, how BM-MSC lineage commitment is regulated remains less well understood. "
[Show abstract] [Hide abstract] ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.0Comments 6Citations
- "The interaction between adipocytes and osteoblasts has traditionally been considered as mutually exclusive such that the transcription factors that induce osteoblastogenesis inhibit adipogenesis and vice versa . Interestingly, there is a significant degree of lineage plasticity between adipocytes and osteoblasts, which share a common progenitor, that further complicates dissecting the relationship between these two cell types in healthy and cancer-containing bone marrow  . Recent evidence suggests, however, that bone marrow adipocytes may derive from a progenitor cell distinct from the progenitor for osteoblasts, chondrocytes, and other bone marrow stromal cells  . "
- [Show abstract] [Hide abstract] ABSTRACT: The transdifferentiation of bone and fat is a new insight in studying the increasingly bone marrow fat in the process of osteoporosis of elderly or menopause crowd which is increasing in prevalence. The loss of bone mass in osteoporosis is multifactorially determined and includes genetic, hormonal and environmental determinants. Although it has long been considered whether the transdifferentiation process does exist in vivo and whether it could be find in the same individual, interaction between skeleton and adipose tissue has been proved pre-clinically and clinically by increasing evidence. Here we focus on the current understanding of the transdifferentiation between bone and fat, the molecular interactions and future clinical implications of recent studies linking the transdifferentiation to bone metabolism diseases. Furthermore, a set of recommendations of bone and fat transdifferentiation on bone metabolism are also presented to facilitate evaluation of this magic process.0Comments 2Citations