Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

Abstract

Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor- γ (PPAR γ ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPAR γ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β -catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

Figure 1

Multilineage differentiation of mesenchymal stem/stromal cells (MSC). Multipotent mesenchymal stem cells (MSC) have been derived from numerous vascularized tissue sources, including bone marrow, adipose, and skeletal muscle tissue, among others. Multilineage differentiation includes osteoblastic, chondrogenic, myogenic, smooth muscle, and neurogenic differentiation. With progressive differentiation toward a mature cell phenotype, often the capacity for differentiation down a competing lineage is lost.

Figure 2

Theoretical inverse relationship between osteogenic and adipogenic programming. Multiple signaling pathways have been demonstrated to preferentially induce osteogenic programming at the expense of adipogenesis, or vice versa. In this regard, the differentiation of an MSC into either an adipocytic or osteoblastic phenotype can be theorized as a seesaw, where induction of one lineage comes at the expense of the other. However, numerous exceptions exist to this simplification.

Figure 3

Schematic of β-catenin dependent and independent Wnt signaling pathways. Wnt signaling transduction occurs via β-catenin dependent or β-catenin independent signaling pathways. In β-catenin dependent signaling, extracellular Wnt ligands bind to the LRP5-Frizzled (Frz) complex to activate intracellular disheveled (DSH). This subsequently inhibits the intracellular complex comprised of axin, glycogen synthase kinase 3 (GSK3), and adenomatosis polyposis coli (APC) protein. This inhibits the cytosolic degradation of β-catenin, which accumulates and is free to enter the nucleus to heterodimerize with lymphoid enhancer-binding factor/T cell factor (LEF/TCF1) and mediate effects of gene transcription. Under the β-catenin independent signaling pathway, a similar transmembrane complex forms between Wnt, Frz, DSH, and Ror2 and activates secondary messengers.

Figure 4

Schematic of Hedgehog signaling pathway. The initially insoluble Hedgehog (HH) ligand precursor undergoes a series of intracellular modifications before reaching an active, multimeric form. Following release from the membrane by Dispatched (DISP), the morphogen binds to Patched (PTCH), which releases Smoothened (SMO) from constitutive inhibition by PTCH. This activates the Gli2/3 complex, which goes on to promote gene expression of Gli1, while repressing the transcriptional repressor Gli3.

Figure 5

Schematic of NELL-1 signaling pathway. NELL-1 is a secreted osteoinductive protein that binds to the cell surface receptor Integrinβ1. Binding to Integrinα3 has also been reported. Multiple intracellular signaling pathways have been shown to increase after NELL-1 stimulation, including MAPK, Hedgehog, and β-catenin dependent Wnt signaling. Although the relative importance of these pathways is still undefined, NELL-1 treatment results in increased Runx2 transcription, Runx2 phosphorylation, and induction of osteogenic programming.