Sonic Hedgehog Promotes Cementoblastic Differentiation via Activating the BMP Pathways

Abstract

Although sonic hedgehog (SHH), an essential molecule in embryogenesis and organogenesis, stimulates proliferation of human periodontal ligament (PDL) stem cells, the effects of recombinant human SHH (rh-SHH) on osteoblastic differentiation are unclear. To reveal the role of SHH in periodontal regeneration, expression of SHH in mouse periodontal tissues and its effects on the osteoblastic/cementoblastic differentiation in human cementoblasts were investigated. SHH is immunolocalized to differentiating cementoblasts, PDL cells, and osteoblasts of the developing mouse periodontium. Addition of rh-SHH increased cell growth, ALP activity, and mineralization nodule formation, and upregulated mRNA expression of osteoblastic and cementoblastic markers. The osteoblastic/cementoblastic differentiation of rh-SHH was abolished by the SHH inhibitor cyclopamine (Cy) and the BMP antagonist noggin. rh-SHH increased the expression of BMP-2 and -4 mRNA, as well as levels of phosphorylated Akt, ERK, p38, and JNK, and of MAPK and NF-κB activation, which were reversed by noggin, Cy, and BMP-2 siRNA. Collectively, this study is the first to demonstrate that SHH can promote cell growth and cell osteoblastic/cementoblastic differentiation via BMP pathway. Thus, SHH plays important roles in the development of periodontal tissue, and might represent a new therapeutic target for periodontitis and periodontal regeneration.

M2 Macrophages Enhance the Cementoblastic Differentiation of Periodontal Ligament Stem Cells via the Akt and JNK Pathways

“…Previously, the BMP/Smad and Akt/MAPK/NF-κB pathways were found to contribute to rh-SHH-induced osteoblastic or cementoblastic differentiation [23], and a stepwise pathway involving Akt/JNK or Akt-MAPK/ERK was demonstrated to regulate cell inflammation, an undifferentiated state and viability [25,59]. These findings are consistent with our data that JNK activation induced by M2 Mφs was inhibited by the addition of Akt inhibitor (Fig.…”

“…Given that the Wnt/β-catenin, Akt, TGF-β/Smad, BMP/Smad, and MAPK pathways have been demonstrated to regulate the osteogenesis/cementogenesis process [20][21][22][23][24][25][26][27][28], key genes involved in the above pathways were selected to screen the potential pathways that regulate M2 Mφ-enhanced cementoblastic differentiation. When the expression of the selected genes in CM-M2-treated PDLSCs (M2 group) and untreated PDLSCs (Control group) was analyzed using qRT-PCR, the pathway-related genes that were differentially expressed between the two groups were plotted in a heatmap (Fig.…”

Sonic Hedgehog Signaling and Tooth Development

“…Recent studies have demonstrated that growth factors, including BMPs and transforming growth factor-beta, mediate reciprocal epithelial-mesenchymal interactions during tooth root development [21,45,46,59]. It has also been shown that the epithelial cells of the HERS secrete Shh [42,43,60]. In this process, via Shh signaling, dental mesenchymal cells expressing Ptch are stimulated to form the root dentin [35,36].…”

Intermittent parathyroid hormone promotes cementogenesis in a PKA‐ and ERK1/2‐dependent manner

“…ERK‐1/2 are widely investigated as key regulators in bone formation . Recent researches showed that they are important intermediary signaling molecules for cementoblastic differentiation and cementogenesis . Inhibition of ERK1/2 phosphorylation downregulated the expression of cementum attachment protein and cementum protein‐1 .…”