Abstract
Parathyroid hormone (PTH) exerts dual effects, anabolic or catabolic, on bone when administrated intermittently or continuously, via mechanisms that remain largely unknown. PTH binding to cells induces PTH-responsive genes including primary response genes (PRGs). PRGs are rapidly induced without the need for de novo protein synthesis, thereby playing pivotal roles in directing subsequent molecular responses. In this study, to understand the role of PRGs in mediating osteoblastic cellular responses to PTH, we investigated whether various durations of PTH differentially induce PRGs in primary osteoblasts and MC3T3-E1. Nurr1 and RANKL, PRGs known for their anabolic and catabolic roles in bone metabolism respectively, presented distinctive transient vs. sustained induction kinetics. Corroborating their roles, maximum induction of Nurr1 was sufficiently achieved by brief PTH in as little as 30 minutes and continued beyond that, while maximum induction of RANKL was achieved only by prolonged PTH over 4 hours. Our data suggested distinctive regulatory mechanisms for Nurr1 and RANKL: PKA-mediated chromatin rearrangement for transcriptional regulation of both PRGs and ERK-mediated transcriptional regulation for RANKL but not Nurr1. Lastly, we classified PRGs into two groups based on the induction kinetics: The group that required brief PTH for maximum induction included Nur77, cox-2, and Nurr1, all of which are reported to play roles in bone formation. The other group that required prolonged PTH for maximum induction included IL-6 and RANKL, which play roles in bone resorption. Together, our data suggested the crucial role of PRG groups in mediating differential osteoblastic cellular responses to intermittent vs. continuous PTH. Continued research into the regulatory mechanisms of PKA and ERK for PRGs will help us better understand the molecular mechanisms underlying the dual effects of PTH, thereby optimizing the current therapeutic use of PTH for osteoporosis.
Highlights
Parathyroid hormone (PTH), an endocrine regulator of calcium homeostasis, exerts paradoxical dual effects, anabolic or catabolic, on bone metabolism depending on whether it is administered intermittently or continuously [1, 2]
We tested whether Nurr1 and RANKL were PTH-induced primary response genes (PRGs) in primary calvarial osteoblasts and MC3T3 osteoblastic cells
The PTH-induced mRNA expression levels of both Nurr1 and RANKL were not attenuated by the pre-treatment of cycloheximide (CHX), a protein synthesis inhibitor; Nurr1 and RANKL were confirmed as PTH-induced osteoblastic PRGs (Fig 1A, S1 Fig)
Summary
Parathyroid hormone (PTH), an endocrine regulator of calcium homeostasis, exerts paradoxical dual effects, anabolic or catabolic, on bone metabolism depending on whether it is administered intermittently or continuously [1, 2]. PTH increases bone turnover, intermittent PTH upregulates osteoblast differentiation and function more than osteoclastogenesis, leading to net bone gain. PRGs are genes that are rapidly induced without the need for de novo protein synthesis [7]. They affect subsequent molecular responses by playing versatile roles as transcription factors, enzymes, signaling mediators, and cytokines in various types of cells, such as neuronal cells, cardiac cells, and immune cells [8,9,10,11]. RANKL, a member of the tumor necrosis factor (TNF) cytokine family, is a well-known master regulator of osteoclastogenesis [15]
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