Polo Like Kinase 4 (PLK4) impairs human bone marrow mesenchymal stem cell (BMSC) viability and osteogenic differentiation.

Human bone marrow mesenchymal stem cell (hBMSC) viability and osteogenic differentiation play a critical role in bone disorders such as osteoporosis. In the present study, we identified the aberrant PLK4 upregulation in osteoporosis and downregulation in BMSCs during osteogenic differentiation. In isolated hBMSCs, PLK4 overexpression significantly inhibited, whereas PLK4 knockdown promoted cell viability and hBMSC osteogenic differentiation. For molecular mechanism, PLK4 overexpression decreased, whereas PLK4 knockdown increased WNT1 and ß-catenin protein levels and the phosphorylation of Smad1/5/8. The Wnt/ß-catenin signaling antagonist Dickkopf 1 (DKK1) or the BMP-Smads antagonist LDN193189 dramatically suppressed hBMSC osteoblast differentiation, and partially attenuated the promotive effects of PLK4 knockdown on hBMSC osteogenic differentiation. Altogether, PLK4 overexpression impairs hBMSC viability and osteogenic differentiation potential, possibly through the Wnt/ß-catenin signaling and BMP/Smads signaling.

Expression patterns of transcription factor PPARγ and C/EBP family members during in vitro adipogenesis of human bone marrow mesenchymal stem cells.

In the past decades increasing lines of evidence have demonstrated that adipose tissue, as an endocrine organ plays a central role in metabolic homeostasis and its related maladies. CCAAT/enhancer-binding protein (C/EBP) family members and the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) were known to be the vital transcription factors in the regulation of adipogenesis. However, the exact mechanism for increased marrow fat in patients with bone metabolic diseases, such as osteoporosis, is still poorly understood. Herein, we studied the expression pattern of PPARγ and C/EBPs in human bone marrow mesenchymal stem cell (hBMSC) adipogenesis and evaluated the effects of individual components of an adipogenic cocktail on the differentiation and transcription factor expression. We furthermore examined whether the ERK signaling pathway was involved in mediating these effects. These findings showed that C/EBPß and C/EBPδ were detected in undifferentiated hBMSC and maintained during the whole process of adipogenesis, and could initiate the expression of PPARγ1 under the treatment of dexamethasone and IBMX. Subsequently, the activation of PPARγ1 by indomethacin, its exogenous ligand, activated C/EBPα, which, together with IBMX, up-regulated PPARγ2 expression and therefore the fullest adipogenesis. Insulin and its downstream signal pathway extracellular signal-regulated kinases (ERK), however, were found not necessary for hBMSC adipogenesis. Our results revealed some unique characteristics of human adipocyte formation, which may help to understand the molecular mechanisms of bone marrow adipogenesis and give insights into the treatment of osteoporosis.