Originally, leptin was described as a product of adipocytes that acts on the hypothalamus to regulate appetite. However, subsequently, it has been shown that leptin receptors are distributed widely and that leptin has diverse functions, including promotion of hemopoietic and osteoblastic differentiation. It has been recognized for some time that both serum leptin and bone mass are correlated positively to body fat mass and, recently, we have shown a direct positive relationship between serum leptin and bone mass in nonobese women. We now report that leptin inhibits osteoclast generation in cultures of human peripheral blood mononuclear cells
Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D-mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast.Introduction: Vitamin D stimulates osteoclastogenesis acting through its nuclear receptor (VDR) in immature osteoblast/stromal cells. This mobilization of calcium stores does not occur in a random manner, with bone preferentially removed from cancellous bone. The process whereby the systemic, humoral regulator is targeted to a particular region of the skeleton is unclear. Materials and Methods: Bone resorption was assessed in mice with vitamin D receptor transgenically elevated in mature osteoblasts (OSVDR). Vitamin D-mediated osteoclastogenesis was examined in vitro using OSVDR osteoblasts and osteoblastic RANKL: osteoprotegerin (OPG) examined in vivo and in vitro after vitamin D treatment. Results: Vitamin D-mediated osteoclastogenesis was reduced in OSVDR mice on chow and calciumrestricted diets, with effects confined to cancellous bone. OSVDR osteoblasts had a reduced capacity to support osteoclastogenesis in culture. The vitamin D-mediated reduction in OPG expression was reduced in OSVDR osteoblasts in vivo and in vitro, resulting in a reduced RANKL/OPG ratio in OSVDR compared with wildtype, after exposure to vitamin D. Conclusions: Mature osteoblasts play an inhibitory role in bone resorption, with active vitamin D metabolites acting through the VDR to increase OPG. This inhibition is less active in cancellous bone, effectively targeting this region for resorption after the systemic release of activated vitamin D metabolites.
Human osteoclasts can be efficiently generated in vitro from cord blood mononuclear cells and derived CFU-GM colonies. However, CFU-M colonies are poorly osteoclastogenic. Short-term (2-48 h) treatment with GM-CSF stimulates osteoclast formation by proliferating precursors, whereas longer exposure favors dendritic cell formation.Introduction: Osteoclasts (OC) differentiate from cells of the myelomonocytic lineage under the influence of macrophage-colony stimulating factor (M-CSF) and RANKL. However, cells of this lineage can also differentiate to macrophages and dendritic cells (DC) depending on the cytokine environment. The aims of this study were to develop an efficient human osteoclastogenesis model and to investigate the roles of granulocyte macrophage-colony stimulating factor (GM-CSF) and M-CSF in human OC differentiation. Materials and Methods: A human osteoclastogenesis model, using as precursors colony forming unit-granulocyte macrophage (CFU-GM) colonies generated from umbilical cord mononuclear cells cultured in methylcellulose with GM-CSF, interleukin (IL)-3 and stem cell factor (SCF), has been developed. CFU-GM, colony forming unitmacrophage (CFU-M), or mixed colonies were cultured on dentine with soluble RANKL (sRANKL) and human M-CSF with and without GM-CSF. Major endpoints were OC number, dentine resorption, and CD1a ϩ DC clusters. Results: Osteoclast generation from CFU-GM and mixed colonies treated with M-CSF and sRANKL for 7-14 days was highly efficient, but CFU-M colonies were poorly osteoclastogenic under these conditions. Pretreatment of precursors with M-CSF for 7 or 14 days maintained the precursor pool, but OCs were smaller and resorption was reduced. The effect of GM-CSF treatment was biphasic, depending on the timing and duration of exposure. Short-term treatment (2-48 h) at the beginning of the culture stimulated cell proliferation and enhanced OC formation up to 100%, independent of sRANKL. Longer-term GM-CSF treatment in the presence of sRANKL, however, inhibited OC generation with the formation of extensive CD1a ϩ DC clusters, accompanied by downregulation of c-Fos mRNA. Delaying the addition of GM-CSF resulted in progressively less inhibition of osteoclastogenesis. Conclusions: Human CFU-GM, but not CFU-M, progenitors have high osteoclastogenic potential. GM-CSF plays an important role in osteoclastogenesis and has a biphasic effect: Short-term treatment potentiates OC differentiation by proliferating precursors, but persistent exposure favors DC formation.
IL-33 is an important inflammatory mediator in allergy, asthma, and joint inflammation, acting via its receptor, ST2L, to elicit Th₂ cell cytokine secretion. IL-33 is related to IL-1 and IL-18, which both influence bone metabolism, IL-18 in particular inhibiting osteoclast formation and contributing to PTH bone anabolic actions. We found IL-33 immunostaining in osteoblasts in mouse bone and IL-33 mRNA expression in cultured calvarial osteoblasts, which was elevated by treatment with the bone anabolic factors oncostatin M and PTH. IL-33 treatment strongly inhibited osteoclast formation in bone marrow and spleen cell cultures but had no effect on osteoclast formation in receptor activator of nuclear factor-κB ligand/macrophage colony-stimulating factor-treated bone marrow macrophage (BMM) or RAW264.7 cultures, suggesting a lack of direct action on immature osteoclast progenitors. However, osteoclast formation from BMM was inhibited by IL-33 in the presence of osteoblasts, T cells, or mature macrophages, suggesting these cell types may mediate some actions of IL-33. In bone marrow cultures, IL-33 induced mRNA expression of granulocyte macrophage colony-stimulating factor, IL-4, IL-13, and IL-10; osteoclast inhibitory actions of IL-33 were rescued only by combined antibody ablation of these factors. In contrast to osteoclasts, IL-33 promoted matrix mineral deposition by long-term ascorbate treated primary osteoblasts and reduced sclerostin mRNA levels in such cultures after 6 and 24 h of treatment; sclerostin mRNA was also suppressed in IL-33-treated calvarial organ cultures. In summary, IL-33 stimulates osteoblastic function in vitro but inhibits osteoclast formation through at least three separate mechanisms. Autocrine and paracrine actions of osteoblast IL-33 may thus influence bone metabolism.
Human parechovirus types 1–16 (HPeV1–16) are positive strand RNA viruses in the family Picornaviridae. We investigated a 2015 outbreak of HPeV3 causing illness in infants in Victoria, Australia. Virus genome was extracted from clinical material and isolates and sequenced using a combination of next generation and Sanger sequencing. The HPeV3 outbreak genome was 98.7% similar to the HPeV3 Yamagata 2011 lineage for the region encoding the structural proteins up to nucleotide position 3115, but downstream of that the genome varied from known HPeV sequences with a similarity of 85% or less. Analysis indicated that recombination had occurred, may have involved multiple types of HPeV and that the recombination event/s occurred between March 2012 and November 2013. However the origin of the genome downstream of the recombination site is unknown. Overall, the capsid of this virus is highly conserved, but recombination provided a different non-structural protein coding region that may convey an evolutionary advantage. The indication that the capsid encoding region is highly conserved at the amino acid level may be helpful in directing energy towards the development of a preventive vaccine for expecting mothers or antibody treatment of young infants with severe disease.
In bone, depletion of osteoclasts reduces bone formation in vivo, as does osteal macrophage depletion. How osteoclasts and macrophages promote the action of bone forming osteoblasts is, however, unclear. Since recruitment and differentiation of multi-potential stromal cells/mesenchymal stem cells (MSC) generates new active osteoblasts, we investigated whether human osteoclasts and macrophages (generated from cord blood-derived hematopoietic progenitors) induce osteoblastic maturation in adipose tissue-derived MSC. When treated with an osteogenic stimulus (ascorbate, dexamethasone and β-glycerophosphate) these MSC form matrix-mineralising, alkaline phosphatase-expressing osteoblastic cells. Cord blood-derived progenitors were treated with macrophage colony stimulating factor (M-CSF) to form immature proliferating macrophages, or with M-CSF plus receptor activator of NFκB ligand (RANKL) to form osteoclasts; culture medium was conditioned for 3 days by these cells to study their production of osteoblastic factors. Both osteoclast- and macrophage-conditioned medium (CM) greatly enhanced MSC osteoblastic differentiation in both the presence and absence of osteogenic medium, evident by increased alkaline phosphatase levels within 4 days and increased mineralisation within 14 days. These CM effects were completely ablated by antibodies blocking gp130 or oncostatin M (OSM), and OSM was detectable in both CM. Recombinant OSM very potently stimulated osteoblastic maturation of these MSC and enhanced bone morphogenetic protein-2 (BMP-2) actions on MSC. To determine the influence of macrophage activation on this OSM-dependent activity, CM was collected from macrophage populations treated with M-CSF plus IL-4 (to induce alternative activation) or with GM-CSF, IFNγ and LPS to cause classical activation. CM from IL-4 treated macrophages stimulated osteoblastic maturation in MSC, while CM from classically-activated macrophages did not. Thus, macrophage-lineage cells, including osteoclasts but not classically activated macrophages, can strongly drive MSC-osteoblastic commitment in OSM-dependent manner. This supports the notion that eliciting gp130-dependent signals in human MSC would be a useful approach to increase bone formation.
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