Abstract
The four R-spondins (RSPOs) and their three related receptors, LGR4, 5 and 6, have emerged as a major ligand-receptor system with critical roles in development and stem cell survival. However, the exact roles of the RSPO-LGR system in osteogenesis remain largely unknown. In the present study, we showed that RSPO3-shRNA increased the osteogenic potential of human adipose-derived stem cells (hASCs) significantly. Mechanistically, we demonstrated that RSPO3 is a negative regulator of ERK/FGF signalling. We confirmed that inhibition of the ERK1/2 signalling pathway blocked osteogenic differentiation in hASCs, and the increased osteogenic capacity observed after RSPO3 knockdown in hASCs was reversed by inhibition of ERK signalling. Further, silencing of LGR4 inhibited the activity of ERK signalling and osteogenic differentiation of hASCs. Most importantly, we found that loss of LGR4 abrogated RSPO3-regulated osteogenesis and RSPO3-induced ERK1/2 signalling inhibition. Collectively, our data show that ERK signalling works downstream of LGR4 and RSPO3 regulates osteoblastic differentiation of hASCs possibly via the LGR4-ERK signalling.
Highlights
Knockdown of rspo[3] causes ventral oedema and vascular defects in Xenopus[20]
The present study demonstrated that RSPO3 plays an important role in osteogenic commitment of human adipose-derived stem cells (hASCs)
When cultured in osteogenic medium, we found that RSPO3 deficiency could promote osteogenic differentiation of hASCs significantly, with increased alkaline phosphatase (ALP) activity, matrix mineralization capacity, and mRNA expression of RUNX2, ALP, and OCN
Summary
Knockdown of rspo[3] causes ventral oedema and vascular defects in Xenopus[20]. Rspo3-null mice suffer from severe vascular defects and are embryonic lethal[21]. RSPO-LGR was demonstrated play critical roles in development and stem cell survival. The exact roles of this ligand-receptor system in osteogenesis remain largely unknown. We first identified that RSPO3 is a negative regulator of hASCs osteogenic differentiation. RSPO3 silencing leads to activation of ERK signalling pathway, which is essential for osteoblast differentiation of hASCs. LGR4 positively regulates osteoblast differentiation of hASCs via ERK signalling pathway. Loss of LGR4 attenuates the enhanced osteogenesis induced by RSPO3 silencing. Our findings suggested that RSPO3 functions as a negative regulator of osteogenesis possibly through a LGR4-ERK dependent mechanism
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