Parathyroid Hormone Signaling in Osteocytes

Abstract

Osteocytes are the most abundant cell type in bone and play a central role in orchestrating skeletal remodeling, in part by producing paracrine‐acting factors that in turn influence osteoblast and osteoclast activity. Recent evidence has indicated that osteocytes are crucial cellular targets of parathyroid hormone (PTH). Here, we will review the cellular and molecular mechanisms through which PTH influences osteocyte function. Two well‐studied PTH target genes in osteocytes are SOST and receptor activator of NF‐κB ligand (RANKL). The molecular mechanisms through which PTH regulates expression of these two crucial target genes will be discussed. Beyond SOST and RANKL, PTH/PTH‐related peptide (PTHrP) signaling in osteocytes may directly influence the way osteocytes remodel their perilacunar environment to influence bone homeostasis in a cell‐autonomous manner. Here, I will highlight novel, additional mechanisms used by PTH and PTHrP to modulate bone homeostasis through effects in osteocytes. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein

“…1A). While these discoveries integrated with and extended several established models of the osteocyte mechanical response (17)(18)(19)(20), we found the loss of sclerostin protein was surprisingly rapid and was likely wholly distinct from the well-characterized transcriptional regulation of the Sost gene, which occurs on the hours timescale (11,12). Despite its physiologic significance, surprisingly little is known about the post-translational control of sclerostin protein.…”

“…Despite their clinical application, little is known about how mechanical load and PTH exposure, two disparate bone anabolic signals, regulate sclerostin protein bioavailability. To date, the regulation of sclerostin abundance has been exclusively attributed to the transcriptional downregulation of the Sost gene that occurs hours after mechanical load or PTH exposure (11,12).…”

Teriparatid – Das molekulare und klinische Profil bei der Therapie der Osteoporose

“…Die Generierung kürzerer Polypeptide erlaubt schon rein pharmakologisch eine verkürzte Rezeptorstimulation und damit einen osteoanabolen Stimulus mit vergleichsweise geringer Osteoklasten-Aktivierung. Eine sehr wichtige Wirkung des PTH ist die Hemmung der Sclerostin-Produktion in Osteozyten und damit die permissive Wirkung für die osteogenen Signale des wnt-Signalwegs, sowie die Beeinflussung der RANKL-Produktion im Osteozyten [6].…”

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause

“…and PTHrP stimulate the generation of cAMP, the most prominent second messenger down-stream of the PTH/PTHrP receptor, that is required for activation of protein kinase A (PKA). The subsequent phosphorylation of SIK2 and SIK33 inhibits the cellular activity of these salt-inducible kinases, thereby reducing phosphorylation of SIK substrates, including class IIa HDACs and CRTC family proteins (for review see [4][5][6]). Here, we review several rare genetic defects that can lead to similar shortening of metatarsals and/or -tarsals high-lighting the particularly sensitive involvement of the cAMP/ PKA signaling pathway in these skeletal elements.…”