Abstract
Bone marrow-derived mesenchymal stromal cells (hMSCs) are capable of differentiating into the osteogenic lineage, and for osteogenic differentiation, mechanical loading is a relevant stimulus. Mechanotransduction leads to the formation of second messengers such as cAMP, cGMP, or Ca2+ influx resulting in the activation of transcription factors mediating gene regulation. The second messengers cAMP and cGMP are degraded by phosphodiesterase isoenzymes (PDE), but the role of these enzymes during osteogenic differentiation or mechanotransduction remains unclear. Here, we focused on the isoenzyme phosphodiesterase 10A (PDE10A) and its role during osteogenic commitment and mechanotransduction. We observed a time-dependent decrease of PDE10A expression in hMSC undergoing differentiation towards the osteogenic lineage. PDE10A inhibition by papaverine diminished osteogenic differentiation. While applying mechanical strain via cyclic stretching of hMSCs led to an upregulation of PDE10A gene expression, inhibition of PDE10A using the drug papaverine repressed expression of mechanoresponsive genes. We conclude that PDE10A is a modulator of osteogenic differentiation as well as mechanotransduction in hMSCs. Our data further suggests that the relative increase of cAMP, rather than the absolute cAMP level, is a key driver of the observed effects.
Highlights
Bone is a complex tissue that is formed by mesoderm-derived stem cells during development
phosphodiesterase 10A (PDE10A) mRNA was detectable, both in human primary MSC and primary MSCs isolated from murine calvariae (Figure 1) as well as murine preosteoblastic cell line MC3T3
Total RNA and whole-cell lysates were prepared from cells harvested after 1, 10, 20, and 30 days, and the expression of PDE10A was analyzed by qPCR and Western blot
Summary
Bone is a complex tissue that is formed by mesoderm-derived stem cells during development. Core osteogenic signaling cascades orchestrate these processes, e.g., the wnt/frizzled pathway, the TGFβ-related family of receptors with bone morphogenetic proteins (BMPs) as ligands, and type 1 parathyroid hormone receptor (PTH1R) signaling as induced by parathyroid hormone (PTH) and PTH-related peptide (PTHLH). The latter represents an important pathway that is linked to the production of the second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). The cAMP-response element-binding protein (CREB) is phosphorylated and binds to respective CRE elements in the promoters of target genes like c-fos and c-jun, RUNX2 (runx-related transcription factor 2), and BMPR2 (bone morphogenetic protein receptor II). All these factors support bone formation and fracture healing [4, 5]
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