Prostaglandin E2: From Clinical Applications to Its Potential Role in Bone- Muscle Crosstalk and Myogenic Differentiation

Abstract

Prostaglandin E2 (PGE2), a prostanoid synthesized from arachidonic acid via the cyclooxygenase pathway, is a modulator of physiological responses including inflammation, fever, and muscle regeneration. Several patents have been filed that are related to PGE2, one of them being directly related to skeletal muscles. In this report, we first summarize the key patents describing inventions for the utilization of PGE2 for either diagnostic or therapeutic purposes, including skeletal muscle. In the second part of our work we present new and exciting data that demonstrates that PGE2 accelerates skeletal muscle myogenic differentiation. Our discovery resulted from our recent and novel concept of bone-muscle crosstalk. Bone and muscle are anatomically intimate endocrine organs and we aimed to determine whether this anatomical intimacy also translates into a biochemical communication from bone cells to muscle cells at the in vitro level. The effects of MLO-Y4 osteocyte-like cell conditioned medium (CM) and three osteocyte-secreted factors, PGE2, sclerostin and monocyte chemotactic protein (MCP-3), on C2C12 myogenic differentiation were evaluated using morphological analyses, a customized 96-PCR gene array, and measurements of intracellular calcium levels. MLO-Y4 CM and PGE2, but not sclerostin and MCP-3, induced acceleration of myogenesis of C2C12 myoblasts that was linked with significant modifications in intracellular calcium homeostasis. This finding should further stimulate the pursuit of new patents to explore the use of PGE2 and the new concept of bone-muscle crosstalk for the development and application of inventions designed to treat muscle diseases characterized by enhanced muscle wasting, such as sarcopenia.

Evaluation of serum myostatin and sclerostin levels in chronic spinal cord injured patients

“…Our data about the supposed correlation between sclerostin and myostatin should be taken cautiously, considering the small sample size. However, assuming the hypothesis of a biochemical cross-talk between the bone and muscle tissue, 12 which could partially explain the mechanisms underlying the observed modifications in these two tissues after SCI, myostatin could be one of the responsible of this cross-talk by the muscle side. However, this is just an hypothesis, and further studies are needed to deeply investigate this possible cross-talk in which other mediators could be involved.…”

“…10,11 In vitro studies suggest the possible existence of a biunivocal cross-talk between the bone and muscle, indicating that factors produced by osteocytes could target muscle and that muscle-derived soluble factors could target bone. 12 It is likely that, although osteocytes and sclerostin are responsible for cross-talk between bone and muscle, satellite cells (at skeletal muscle level) could have a role in the opposite way. [12][13][14][15] Myostatin is a powerful inhibitor of overall muscle differentiation and growth both in vivo and in vitro.…”

“…12 It is likely that, although osteocytes and sclerostin are responsible for cross-talk between bone and muscle, satellite cells (at skeletal muscle level) could have a role in the opposite way. [12][13][14][15] Myostatin is a powerful inhibitor of overall muscle differentiation and growth both in vivo and in vitro. 16 As the inhibition of myostatin pathway facilitates muscle growth, myostatin could be used as a possible biomarker to monitor the evolution of muscular modifications in SCI patients and could also represent a potential therapeutical target.…”

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

“…Biochemical signals emanating from muscle may also play important roles in the effects of muscle contraction by ES on bone. Muscle and bone are intimately associated endocrine organs (34,35). A growing body of evidence indicates that endocrine and paracrine signals derived from muscle (referred to as myokines) modulate bone metabolism (36).…”

Does Defective Bone Lead to Defective Muscle?

“…(11) Conversely, it has recently been shown that bone secretes factors that can target other organs such as pancreas and kidney through relatively bone-specific factors such as osteocalcin and FGF23 (for reviews see Pi and Quarles (12) and Ferron and colleagues (13) ). More recent studies using in vitro approaches suggest that bone may regulate muscle mass and function (14) (Mo CL, Romero-Suarez S, Bonewald LF, Johnson ML, Brotto M, unpublished work). The study by Shen and colleagues (15) in this issue of the JBMR is one of the first that has used in vivo studies to support the concept that bone can target muscle.…”