Defining osteoblast and adipocyte lineages in the bone marrow

Abstract

Bone is a complex endocrine organ that facilitates structural support, protection to vital organs, sites for hematopoiesis, and calcium homeostasis. The bone marrow microenvironment is a heterogeneous niche consisting of multipotent musculoskeletal and hematopoietic progenitors and their derivative terminal cell types. Amongst these progenitors, bone marrow mesenchymal stem/stromal cells (BMSCs) may differentiate into osteogenic, adipogenic, myogenic, and chondrogenic lineages to support musculoskeletal development as well as tissue homeostasis, regeneration and repair during adulthood. With age, the commitment of BMSCs to osteogenesis slows, bone formation decreases, fracture risk rises, and marrow adiposity increases. An unresolved question is whether osteogenesis and adipogenesis are co-regulated in the bone marrow. Osteogenesis and adipogenesis are controlled by specific signaling mechanisms, circulating cytokines, and transcription factors such as Runx2 and Pparγ, respectively. One hypothesis is that adipogenesis is the default pathway if osteogenic stimuli are absent. However, recent work revealed that Runx2 and Osx1-expressing preosteoblasts form lipid droplets under pathological and aging conditions. Histone deacetylase 3 (Hdac3) and other epigenetic regulators suppress lipid storage in preosteoblasts and/or control marrow adiposity. Establishing a better understanding of fat storage in bone marrow cells, as well as the osteoblast-adipocyte relationship within the bone marrow niche is necessary to understand the mechanisms underlying disease- and aging-related marrow fat storage and may lead to the development of new therapeutic targets for "fatty bone" and osteoporosis.

Keywords: Adipocyte; Adipogenesis; Aging; Bone marrow mesenchymal/stromal cell; Marrow fat; Osteoblast; Osteogenesis.

Figure 1

Differentiation of BMSCs to osteogenic and adipogenic lineages. Bone marrow mesenchymal stem cells (BMSCs) are signaled to differentiate to osteoblasts by transcription factors such Runx2 and Osx1 or to adipocytes by Pparγ and c/EBPα. BMSC-derived osteoblasts can further differentiate into mature osteocytes or may become lipid-storing cell types. This diagram illustrates a potential lineage-switching mechanism between osteoblasts and adipocytes as well as a reduction of lipid storage within osteogenic cells by histone deacetylase 3 (Hdac3) and its associated cofactors.

Figure 2

Shift of cellular energetics profiles through BMSC differentiation. The progenitor BMSC population is highly glycolytic and dependent on glucose for energy metabolism. As BMSCs commit to osteogenesis, the energy demands of osteoid production require metabolic processes that generate more ATP—e.g., the metabolism of fatty acids for oxidative phosphorylation. Mature osteoblasts utilize a combination of glycolysis and oxidative phosphorylation to meet their energy needs, but this energetic balance must be tightly regulated to reduce reactive oxygen species (ROS) generation and subsequent cellular damage. In contrast to BMSCs, mature adipocytes generate much of their ATP from fatty acid oxidation and oxidative phosphorylation. The metabolic profile of the lipid-positive pre-osteoblast is still in question, but the intermediate morphology of this cell type suggests that it may use both energetic processes and may potentially store lipid droplets for fatty acid metabolism under high energy demand.

Figure 3

Marrow fat accumulates with age in tibiae from female C57BL/6 mice. Osmium tetroxide-stained murine tibias imaged by micro-computed tomography show proximal and distal marrow adipose tissue at a) 4 months, b) 13 months, and c) 22 months of age. Each image is from a different mouse.