Figure 9: Model showing PTH signaling via inhibition of SIK2 in osteocytes.
From: SIKs control osteocyte responses to parathyroid hormone
In the absence of PTH signaling, SIK2 tonically phosphorylates its substrates HDAC4/5 and CRTC2, leading to their cytoplasmic retention via binding to 14-3-3 chaperones. PTH signaling leads to PKA-mediated phosphorylation of SIK2, which inhibits its cellular activity. This in turn reduces phosphorylation of HDAC4/5 and CRTC2, leading to their dephosphorylation by an unknown phosphatase (ppase), and subsequent nuclear translocation. Small molecule SIK inhibitors (YKL-05-093 and YKL-05-099) mimic the effects of PTH by directly blocking SIK2 kinase activity. In the nucleus, HDAC4/5 block MEF2C-driven SOST expression, while CRTC2 enhances CREB-mediated RANKL gene transcription. PTH-induced reductions in sclerostin contribute to increased bone formation, while PTH-induced increases in RANKL drive increased bone resorption.
