PTH deletion ameliorates the anomalies of Fgf23-deficient mice by suppressing elevated Vitamin D and calcium levels
Fibroblast Growth Factor 23 (FGF23) is a key regulator of calcium and phosphate homeostasis. Fgf23-deficient mice exhibit an elevated serum level of 1,25 dihydroxyvitamin D (1,25(OH)2D), calcium, phosphate and a decreased PTH level. As PTH is known to increase 1,25(OH)2D and calcium level, the authors of a recent study [1] hypothesized that PTH deletion in a Fgf23 deficient background could supress these vitamin D, ion and PTH abnormal levels, and could ameliorate their negative effects on soft tissue atrophies and skeletal abnormalities.
Efficacy of serotonin inhibition in mice models of bone loss
tudying the role played by gut serotonin in bone physiology is an important issue to tackle from a medical perspective.
A recent study showed that decreasing gut-derived serotonin synthesis by utilization of a pharmacological inhibitor of tryptophan hydroxylase 1 (Tph1) could prevent and treat ovariectomy-induced osteoporosis in mice and rats. In this study [1], the authors defined the minimal concentration of this inhibitor (LP533401) to significantly increase bone mass and showed that its anabolic effect persists upon interruption.
Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts
Osteoarthritis (OA) is characterized by the progression of cartilage degeneration associated with remodeling of the subchondral bone. This remodeling is the consequence of an increased bone resorption over bone formation due to abnormal osteoblast phenotype. Bone resorption is mainly due to the differentiation and the activation of osteoclasts by the RANK-RANKL signalling pathway. RANKL is produced by osteoblasts. In osteoarthritis patients, RANKL is thought to be overexpressed, like MMP-2 and MMP-9, two metalloproteases implicated in collagen degradation. This specific degradation favors bone resorption.
NF-κB inhibitors may represent an interesting strategy in osteoporosis
NF-κB is a family of transcription factors that regulates many important biological processes including immunity and inflammation. In the bone, NF-κB mediates the effect of RANK in osteoclasts. The classic NF-κB pathway activation is regulated by IKK-β which phosphorylates IκB. Once phosphorylated, IκB is targeted to proteasomal degradation and releases NF-κB. Then NF-κB enters the nucleus to regulate the transcription of its target genes. Whereas NF-κB inhibition has been shown to reduce osteoclast formation, its effect on osteoblasts is not well studied. Recently, it was shown that transgenic mice expressing a dominant negative form of IKK in mature osteoblasts had increased bone mineral density and bone volume. These results question the potential interest of the emerging NF-κB inhibitors in treating postmenopausal osteoporosis.
Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment
The mechanical performance of bone and its potential fragility depend not only on bone volume, shape and microarchitecture but also on its intrinsic material properties. Bone material consists of a collagen-rich organic matrix with small plate-shaped mineral hydroxyapatite crystals embedded in it. The mineral density distribution, as well as the shape, size, and arrangement of the mineral crystals, have a major influence on the mechanical behavior of the bone material. Strontium ranelate has been shown to increase bone mass in postmenopausal osteoporosis patients and to reduce fracture risk. Strontium ranelate exerts these effects in part by promoting osteoblast activity and decreasing bone resorption. In vitro studies have demonstrated that strontium could be incorporated within hydroxyapatite crystal in replacement of calcium.
 Download here the slide set presented by Prof. Friedlander, on Thursday, November 10th. |
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