Abstract
Human mesenchymal stem cells (hMSCs) can differentiate into osteoblasts and are regulated by chemical cues. The recombinant N-terminal (1–34 amino acids) fragment of the parathyroid hormone (PTH (1–34)) is identified to promote osteogenesis. The osteoanabolic effects of intermittent PTH (1–34) treatment are linked to a complex consisting of signaling pathways; additionally, protein kinase C (PKC) act as mediators of multifunctional signaling transduction pathways, but the role of PKC δ (PKCδ), a downstream target in regulating osteoblast differentiation during intermittent administration of PTH (1–34) is less studied and still remains elusive. The purpose of this study is to examine the role of PKCδ during intermittent and continuous PTH (1–34) administration using osteoblast-lineage-committed hMSCs. Relative gene expression of osteoblast-specific genes demonstrated significant upregulation of RUNX2, type I Collagen, ALP, and Osterix and increased alkaline phosphatase activity in the presence of PTH (1–34). Intermittent PTH (1–34) administration increased PKC activity at day 7 of osteogenic differentiation, whereas inhibition of PKC activity attenuated these effects. In addition, the specific isoform PKCδ was activated upon treatment. These findings demonstrate that intermittent PTH (1–34) treatment enhances the osteogenesis of hMSCs by upregulating osteoblast-specific genes via PKCδ activation.
Highlights
Bone homeostasis is achieved by a balance between bone formation and bone resorption
The purpose of this study is to investigate the role of protein kinase C (PKC) signaling in both intermittent and continuous parathyroid hormone (PTH) treatment during the osteogenic differentiation of human MSCs, and to identify the functional role of PKC δ (PKCδ) in intermittent PTH (1–34)-enhanced osteogenesis
Osteogenic differentiation after PTH (1–34) treatment was assessed by measuring the expression of early osteoblast-specific genes including RUNX2, COLIa1, Alkaline Phosphatase (ALP), and Osterix by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and osteoblast activity by ALP staining
Summary
Bone homeostasis is achieved by a balance between bone formation and bone resorption. The rate and quality of bone formation depends on osteoblast activity, during which mineralized matrix components are secreted. Bone resorption depends on osteoclast activity to degrade tissues. An imbalance between these processes can lead to osteoporosis. The most common treatment for osteoporosis is anti-resorptive agents that inhibit osteoclast activity. Another therapeutic option, especially for severe cases, is teriparatide, a synthetic and active fragment of parathyroid hormone (PTH), comprising the N-terminal 1–34 amino acids (PTH (1–34)) [1,2]. The intermittent administration of this recombinant form of human PTH has been demonstrated to stimulate more bone formation than bone resorption, increasing the mineral density. The associated mechanisms are poorly understood [3,4]
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