Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies.

Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

The acute inflammatory response to copper(II)-doped biphasic calcium phosphates.

Infection and inflammation are two key features to consider to avoid septic or aseptic loosening of bone-implanted biomaterials. In this context, various approaches to fine-tune the biomaterial's properties have been studied in order to modulate the crosstalk between immune and skeletal cells. Cation-doping strategies for tuning of calcium phosphates properties has been evidenced as a promising way to control the biomaterial-induced inflammatory process, and thus improving their osteoimmunomodulatory properties. Copper(II) ions are recognized for their antibacterial potential, but the literature on their impact on particulate material-induced acute inflammation is scarce. We synthesized copper(II) ions-doped biphasic calcium phosphate (BCP), intended to exhibit osteoimmunomodulatory properties. We addressed in vitro, for the first time, the inflammatory response of human primary polymorphonuclear neutrophils (PMNs) to copper(II) ions-doped or undoped (BCP) powders, synthesized by an original and robust wet method, in the presence or absence of LPS as a costimulant to mimic an infectious environment. ELISA and zymography allowed us to evidence, in vitro, a specific increase in IL-8 and GRO-α secretion but not MIP-1ß, TNF-α, or MMP-9, by PMNs. To assess in vivo relevance of these findings, we used a mouse air pouch model. Thanks to flow cytometry analysis, we highlighted an increased PMN recruitment with the copper(II) ions-doped samples compared to undoped samples. The immunomodulatory effect of copper(II) ions-doped BCP powders and the consequent induced moderate level of inflammation may promote bacterial clearance by PMNs in addition to the antimicrobial potential of the material. Copper(II) doping provides new insights into calcium phosphate (CaP)-based biomaterials for prosthesis coating or bone reconstruction by effectively modulating the inflammatory environment.

[Characteristics of testosterone binding to plasma proteins during the sexual cycle in a seasonally-reproductive animal, the male viviparous lizard]. / Particularité de la liaison de la testostérone aux protéines plasmatiques au cours du cycle sexuel chez un animal à reproduction saisonnière, le lézard vivipare mâle.

Plasma testosterone binding activity was determined by an equilibrium dialysis method in the male of Lacerta vivipara during the annual cycle of activity (from March to September). Capacity showed significant variations during the sexual cycle although affinity remained constant. The variations of capacity were then compared with plasma testosterone levels measured by radioimmunoassay and plasma proteins content measured by the Lowry method. The three parameters showed parallel seasonal evolution except in May-June when binding activity increased although plasma testosterone and protein levels fell. The physiological meaning of this conspicuous phenomenon is discussed=an active mechanism of strengthening of the atrophy of accessory sexual organs is hypothesized. Furthermore, the increase of the binding activity which occurs in autumn and is parallel to the levels of testosterone must prevent these accessory organs from a full resumption of activity before the retreat since the lizard is a hibernating animal. These results emphasize the key role played by specific plasma binding proteins in the modulation of steroid hormone action.

[Binding of testosterone to plasma proteins in the viviparous male lizard]. / Liaison de la testostérone aux protéines plasmatiques chez le lézard vivipare mâle.

Testosterone binding to plasma proteins has been analyzed in the viviparous lizard by electrophoresis at steady state conditions and by equilibrium dialysis. Two binding systems are involved. The first system (S1) binds estradiol and testosterone, it is Sex Binding Protein like. The second one binds testosterone and dihydrotestosterone; the mains competitors are C21 steroids: progesterone and cortisone; estradiol doesn't perturb the equilibrium; this system is Corticosteroid Binding Globulin like. Androstenedione doesn't seem to be bound by these two systems. The high affinity (KA 4 degrees C = 1.28 X 10(8) M-1) and the high capacity (N = 1,18 X 10(-5) mole/litre) suggest that it is the second system that supports the main transport, buffer, reservoir role in the blood of viviparous lizard.