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 (PPARγ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPARγ 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.

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

“…It is likely that NF-kB regulates osteogenesis in a Runx2-independent pathway, such as by b-catenin signaling. 36 In other studies, the suppression of NF-kB promoted osteogenesis in primary bone marrow-derived MSCs and conditional NF-kB-deficient mice. 31 The suppressive effects of NF-kB on osteogenesis are mediated by direct upregulation of Smurf1/2 expression to enhance b-catenin degradation.…”

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

“…Bone morphogenetic proteins (BMPs) are extracellular cytokines originally isolated from bone extracts and have been found to induce ectopic chondrogenesis and osteoblastogenesis 6. It has been reported that the BMP‐2, BMP‐4, BMP‐6, BMP‐7, and BMP‐9 subtypes promote osteogenic commitment, as well as terminal osteogenic differentiation in MSCs 7.…”

“…It has been reported that the BMP‐2, BMP‐4, BMP‐6, BMP‐7, and BMP‐9 subtypes promote osteogenic commitment, as well as terminal osteogenic differentiation in MSCs 7. Additionally, recombinant human BMP‐2 and BMP‐7 have been clinically applied in various bone disorders 6. However, it has also been demonstrated that BMPs have pro‐adipogenic effects 8.…”

Flavonoids of Herba Epimedii stimulate osteogenic differentiation and suppress adipogenic differentiation of primary mesenchymal stem cells via estrogen receptor pathway

“…Therefore, MSCs can serve as precursors to a variety of mature mesenchymal cell types, including osteoblasts, chondrocytes, myocytes, and many other types of cells (James, 2013). It is important to notice that with the progressive differentiation toward a mature cell phenotype, often the capacity for differentiation into a competing lineage is lost.…”