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    • SC 79 While showing that deletion of EP maintains femur bone

    2021-07-21

    While showing that deletion of EP1 maintains femur bone volume fraction and trabecular bone parameters during aging, perhaps more importantly we have also demonstrated that increased initial BV/TV in EP1 is protective against OVX-induced bone loss. That is, while mice lose an approximately equal percentage of bone volume compared to WT, the relatively higher starting point results in bones that are stronger, and therefore less likely to fracture. Indeed, vertebral fractures are the most common osteoporotic fracture [18], [19], and increase the risk for a subsequent vertebral or non-vertebral fracture [20], [21], [22]. Identification of EP1 loss of function as a mechanism to maintain vertebral bone density has profound implications for future osteoporosis treatments. We have determined that EP1 modulates bone mass by regulating bone formation, but not bone resorption. This distinction is important since normal bone homeostasis requires an appropriate balance between bone formation and bone resorption, with un-coupling of these processes leading to pathologic bone changes including osteoporosis. The phenomenon of elevated bone formation with un-changed bone resorption in mice resulted in resistance to ovariectomy-induced bone loss. Our findings established that the increase in bone formation rate in mice was independent of estrogen status; bone formation was similarly increased in sham operated and OVX mice. These data suggest that inhibition of EP1 signaling may be a suitable target for the treatment of osteoporosis, although further studies are needed to elucidate the mechanism of EP1 effects on bone formation. PGE2 has been identified as a central player in injury and repair through the regulation of murine stem and progenitor cell populations [23]. PGE2 stimulation of EP2/4 stabilizes β-catenin, resulting in stem cell proliferation and differentiation [23], [24]. In contrast to EP2/4, which promote osteoblast differentiation [2], [4], EP1 negatively regulates osteoblast differentiation, which may in turn, maintain the stem cell population, and act as a ‘brake’ to slow osteogenic differentiation of stem cells. While this hypothesis is speculative, it is well supported by many other findings. EP1 stimulates fibronectin expression, which helps to maintain osteoprogenitors in a more ‘stem-like’ state [25]. Furthermore, EP1 activates AKT, leading to regulation of FoxO transcription factors, which maintain hematopoietic stem SC 79 in a less mature state [26]. Therefore, EP1 may be a key negative regulator in progression of stem cell differentiation, acting to maintain stem cells in a less differentiated state, as a mechanism to balance the physiological and pathological aspects of PGE2 signaling; however, further studies are necessary to clarify the role of EP1 in stem cell function. Based on the clear role for EP1 in bone homeostasis and regeneration, further studies to define the downstream targets of EP1 will be critical to developing novel ways to treat osteoporosis and accelerate fracture repair. Specific agonists have been developed to target EP2 and EP4 receptors, demonstrating that these structurally related receptor subtypes are individually targetable. An issue with the EP2 and EP4 agonists was toxicity. Most pharmacologic agents are inhibitors, rather than stimulators of pathways, consistent with an approach that would be necessary for EP1-directed pharmacotherapy. Moreover, mice have normal lifespans, suggesting that inhibition of EP1 would be well tolerated. An alternative approach would be to block EP1 signaling through the inhibition of a downstream target. While these studies identify a critical role for EP1 in the negative regulation of bone formation, several limitations must be considered. In the present study, we use 12-month old mice to determine the effects of EP1 on age-related bone loss. However, given the maximum life-span for C57Bl/6J mice is approximately two years [27], the ‘aged’ mice in our study are comparable to sexually-mature adult humans, but do not necessarily reflect the changes in bone that are associated with elderly. Therefore, future studies to determine the effects of EP1 loss of function on bone maintenance in older months (>18months) are necessary. Male mice were used for aging studies, while female mice were used for OVX experiments. The sexual dimorphism in bone strength and architecture [28], [29] precludes a direct comparison between OVX and aged animals. In addition, the potential effect of genetic drift between WT C57Bl/6J and EP1 mice must be considered, as purchased WT mice rather than littermate controls were used in this study. mice were generated on the C57Bl/6J background and were propagated through homozygous sibling breeding sets, a situation which can lead to natural genetic drift away from the original C57Bl/6J strain, which were purchased from Jackson laboratories and are less likely to experience genetic drift due to the Jackson Genetic Stability Program [30].