RESUMEN
Prostaglandin E2 (PGE2), a major cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis (OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts (EP4LysM) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4LysM mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of platelet-derived growth factor-BB (PDGF-BB) was also lower in the EP4LysM mice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4LysM mice. Finally, we showed that the Gαs/PI3K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.
RESUMEN
RF amide-related peptide 3 (RFRP-3) is a reproductive inhibitor and an endogenous orexigenic neuropeptide that may be involved in energy homeostasis. In this study, we evaluated the effect of acute or chronic RFRP-3 treatment (administered via intraperitoneal injection) on the food intake, meal microstructure and weight of rats, as well as the mechanism through which RFRP-3 is involved in glucose metabolism in the pancreas and glucose disposal tissues of rat in vivo. Our results showed that the intraperitoneal administration of RFRP-3 to rats resulted in marked body mass increased, hyperphagia, hyperlipidemia, hyperglycemia, glucose intolerance, hypoinsulinism, hyperglucagon, and insulin resistance, as well as significant increases in the size of pancreatic islets and the inflammatory reaction. Thus, we strongly assert that RFRP-3 as a novel neuroendocrine regulator involved in blood glucose homeostasis.