It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity

We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-B and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca 2؉ release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.osteoblast ͉ osteoclast ͉ osteoporosis ͉ pituitary hormones ͉ bone density O xytocin (OT), a hypothalamic nanopeptide secreted into the circulation from the posterior pituitary, is indispensable for lactation. It acts on a G protein-coupled receptor (Oxtr), the expression of which in reproductive tissues is regulated by sex steroids and OT. In humans and rodents, plasma OT levels are elevated maximally during suckling (1, 2).Mice lacking OT or its receptor (Oxtr) are unable to lactate, despite unperturbed breast tissue and milk formation (3, 4). Most notably, newborn pups die shortly after birth in the absence of a foster mother postpartum. This effect of OT is exerted peripherally, as the i.p. administration of recombinant OT to OT Ϫ/Ϫ mice rescues milk ejection, allowing the newborn to feed normally. In contrast to the milk ejection defect, no deficits in copulation, gestation, fecundity, or parturition have been noted in either OT Ϫ/Ϫ or Oxtr Ϫ/Ϫ mice, suggesting that these mice are typically eugonadal (5). Furthermore, compound mutants with both the Oxtr and the prostaglandin F2␣ receptor deleted exhibit no defects in parturition, indicating significant redundancy in the birth process per se (5). However, in view of the established pharmacology of circulating OT on the uterine myometrium, the possibility of a physiological action of OT during childbirth cannot be excluded, even without a loss-of-function phenotype.Two other key actions of OT warrant mention: effects on social , behavior and on the regulation of food intake. Male OT Ϫ/Ϫ and Oxtr Ϫ/Ϫ mice show deficits in social recognition, without altered cognition or olfactory learning. That this social amnesia is a central rather than a peripheral action of OT is supported by the observation that recombinant OT injected directly into the amygdala rescues the defect (6). Compared with males, female OT or Oxtr null mice display anxiety and exaggerated stress responses, which are likewise mediated through central OT-ergic neurones (7). OT also is involved in the reg...

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Periodontal disease (PD), or periodontitis, is defined as a bacterially induced disease of the tooth-supporting (periodontal) tissues. It is characterized by inflammation and bone loss; therefore understanding how they are linked would help to address the most efficacious therapeutic approach. Bacterial infection is the primary etiology but is not sufficient to induce the disease initiation or progression. Indeed, bacteria-derived factors stimulate a local inflammatory reaction and activation of the innate immune system. The innate response involves the recognition of microbial components by host cells, and this event is mediated by toll-like receptors (TLRs) expressed by resident cells and leukocytes. Activation of these cells leads to the release of proinflammatory cytokines and recruitment of phagocytes and lymphocytes. Activation of T and B cells initiates the adaptive immunity with Th1 Th2 Th17 Treg response and antibodies production respectively. In this inflammatory scenario, cytokines involved in bone regulation and maintenance have considerable relevance because tissue destruction is believed to be the consequence of host inflammatory response to the bacterial challenge. In the present review, we summarize host factors including cell populations, cytokines, and mechanisms involved in the destruction of the supporting tissues of the tooth and discuss treatment perspectives based on this knowledge.