Prostaglandin E2 Receptors EP2 and EP4 Are Down-regulated during Differentiation of Mouse Osteoclasts from Their Precursors

Abstract

Prostaglandin E 2 (PGE 2 ) has been proposed to be a potent stimulator of bone resorption. However, PGE 2 itself has been shown to directly inhibit bone-resorbing activity of osteoclasts. We examined the role of PGE 2 in the function of mouse osteoclasts formed in vitro. Bone marrow macrophage osteoclast precursors expressed PGE 2 receptors EP1, EP2, EP3␤, and EP4, and the expression of EP2 and EP4 was down-regulated during osteoclastic differentiation induced by receptor activator of NF-B ligand and macrophage colony-stimulating factor. In contrast, functional EP1 was continuously expressed in mature osteoclasts. PGE 2 as well as calcitonin caused intracellular Ca 2؉ influx in osteoclasts. However, PGE 2 and 17-phenyltrinol-PGE 2 (an EP1 agonist) failed to inhibit actin-ring formation and pit formation by osteoclasts cultured on dentine slices. When EP4 was expressed in osteoclasts using an adenovirus carrying EP4 cDNA, both actin-ring and pit-forming activities of osteoclasts were inhibited in an infectious unit-dependent manner. Treatment of EP4-expressing osteoclasts with PGE 2 further inhibited their actin-ring and pitforming activities. Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated. Thus, osteoclast precursors down-regulate their own EP2 and EP4 levels during their differentiation into osteoclasts to escape inhibitory effects of PGE 2 on bone resorption.

Homeobox Protein HB9 Binds to the Prostaglandin E Receptor 2 Promoter and Inhibits Intracellular cAMP Mobilization in Leukemic Cells

“…Additionally, the stimulation of gastric cancer cells with PTGER2 agonists results in significant growth inhibition (35). A similar escape mechanism was described in non-malignant myeloid precursors of osteoclasts that try to escape PGE2-induced inhibition of bone resorption by down-regulation of their PTGER2 receptor (36).…”

“…Hence, Kobayashi et al (36,37) demonstrated that PTGER2 is up-regulated in immature myeloid precursors and thus becomes down-regu- lated after the cells have differentiated into osteoclasts. Thus, further studies will show whether down-regulation of PTGER2 either provokes an escape mechanism from PGE2-derived immunomodulatory effects in the bone marrow niche or modulates differentiation of immature preleukemic cells.…”

Green tea polyphenols mitigate bone loss of female rats in a chronic inflammation-induced bone loss model☆☆☆

“…In general, bone formation and bone resorption occur simultaneously in equilibrium, and they are regulated by systemic hormones (such as vitamin D and parathyroid hormone) [48,49], bone-derived local factors including prostaglandins [48], proinflammatory cytokines [48][49][50], nitric oxide [51] and the function of immune cells [52]. Among the prostaglandin E 2 (PGE 2 ) produced by osteoblastic lineage [53] is a potent local factor stimulating bone resorption both in vivo [54] and in vitro [54,55] in response to the catabolic effects of vitamin D, parathyroid hormone and cytokines [56,57]. In vitro studies [58][59][60] show that effects of PGE 2 on bone formation are biphasic and concentration dependent.…”

Prostaglandin F2α negatively regulates bone resorption in murine osteoclast development

“…EP1 causes elevations in intracellular Ca 2+ by coupling with Gq 13 . Osteoclasts express all PGE 2 receptors, and production of intracellular Ca 2+ through EP1 or production of cAMP and activation of protein kinase A (PKA) through EP2 or EP4 are critical for osteoclast cell differentiation 11,12,14,15 .…”