In Vivo Demonstration that Human Parathyroid Hormone 1–38 Inhibits the Expression of Osteoprotegerin in Bone with the Kinetics of an Immediate Early Gene

Abstract

Osteoprotegerin (OPG) is a potent inhibitor of osteoclast formation and function. To elucidate how OPG is regulated in bone, we examined (1) the expression and localization of OPG protein in bone tissue, (2) the effect of human parathyroid hormone 1-38 (hPTH 1-38) on OPG messenger RNA (mRNA) levels in rat femur metaphyseal and diaphyseal bone, and (3) the effect of hPTH(1-38) on expression of OPG mRNA in cultured osteoblast-like cells derived from the metaphysis and diaphysis, and in ROS 17/2.8 osteosarcoma cells. Because PTH has been shown to stimulate osteoblast activity via the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signal transduction pathway we also investigated whether PTH action on OPG in vivo is dependent on activation of cAMP/PKA pathway. Immunohistochemistry was used to evaluate OPG protein expression and Northern blot hybridization was used to analyze OPG mRNA expression both in vivo and in vitro. Immunohistochemistry of OPG protein expression in the rat distal femur metaphysis revealed that it was localized predominantly in preosteoblasts, osteoblasts, lining cells, and the osteoid layer, with occasional immunoreactivity in osteocytes and cells of the bone marrow. Subcutaneous (sc) administration of a single injection of hPTH(1-38) at 80 g/kg induced a rapid and transient decrease in OPG mRNA expression in both metaphyseal and diaphyseal bone. The decrease in OPG message was evident by 1 h and mRNA levels returned to baseline after 3 h. PTH analog PTH(1-31), which stimulates intracellular cAMP accumulation, inhibited OPG expression, whereas PTH analogs (3-34 and 7-34) that do not stimulate cAMP production had no effect on expression. In contrast to PTH, prostaglandin E 2 (PGE 2 ) had no effect on OPG

Osteocyte Wnt/β-Catenin Signaling Is Required for Normal Bone Homeostasis

“…Conversely, cells of the osteoblast lineage are known to impact osteoclastogenesis in a non-cell-autonomous fashion by expressing the osteoclast differentiation factor RANKL and its decoy receptor OPG (24,46). In line with previous findings by us and others (34,51,71,73), cellular fractionation by sequential digestion of femoral diaphyses revealed that primary osteocytes in skeletally growing mice and mature mice robustly express OPG and RANKL at levels exceeding or comparable to those present in osteoblasts. Although it is currently unclear whether osteocyte-expressed cytokines are indeed released into the lacunar-canalicular network, theoretical models and tracer experiments have demonstrated that small globular proteins of up to 7 nm in diameter and 70 kDa, the estimated size of serum albumin, can pass through the osteocyte canalicular system (60,66,67).…”

The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis

“…Although we did not investigate the mechanisms underlying this phenomenon, we suggest at least two factors that may modulate the bone remodeling balance during the TPTD treatment. First, at a cellular level, the increase in bone-resorptive activity by PTH is believed to be an indirect effect of PTH via the production of local factors, such as RANKL from osteoblasts and/or a transient decrease in the production of osteoprotegerin (OPG), which acts as a decoy receptor for RANKL (18,19). A recent study by Joseph et al (9) demonstrated a circadian rhythm for circulating OPG levels with a daytime increase and nocturnal decrease in healthy subjects.…”

Osteoprotegerin Is the Strongest Predictor for Progression of Arterial Calcification in Peritoneal Dialysis Patients

“…Among the currently known predictors or factors associated with arterial wall calcification, osteoprotegerin (OPG), a protein belonging to the family of tumor necrosis factor receptor, has received special attention due to its wide range of interactions with risk factors of cardiovascular damage, such as inflammation [20], endocrine function [21,] and mineral metabolism. In spite of their value, those previous reports about the relationship of biomarkers with calcification derive from cross-sectional designs [22,23], where OPG was measured at later stages of vascular damage, just when calcification is detected, or from prospective studies with measurement of OPG once, at baseline only [24].…”