ABSTRACT
ERRα is an orphan member of the nuclear receptor family, the complete inactivation of which confers resistance to bone loss induced by ageing and estrogen withdrawal to female mice in correlation with increased bone formation in vivo. Furthermore ERRα negatively regulates the commitment of mesenchymal cells to the osteoblast lineage ex vivo as well as later steps of osteoblast maturation. We searched to determine whether the activities of ERRα on osteoblast maturation are responsible for one or both types of in vivo induced bone loss. To this end we have generated conditional knock out mice in which the receptor is normally present during early osteoblast differentiation but inactivated upon osteoblast maturation. Bone ageing in these animals was similar to that observed for control animals. In contrast conditional ERRαKO mice were completely resistant to bone loss induced by ovariectomy. We conclude that the late (maturation), but not early (commitment), negative effects of ERRα on the osteoblast lineage contribute to the reduced bone mineral density observed upon estrogen deficiency.
Subject(s)
Estrogen Receptor alpha/physiology , Estrogens/deficiency , Osteoblasts/cytology , Osteoporosis/physiopathology , Animals , Cell Lineage , Estrogen Receptor alpha/genetics , Male , Mice , Mice, Knockout , Mice, Transgenic , Osteoporosis/pathology , RabbitsABSTRACT
Osteonecrosis of the femoral head (ONFH) is a disabling disease affecting young adults, which usually leads to the destruction of the hip joint. It is mainly due to an inadequate blood supply that causes the death of osteocytes and bone marrow cells. Joint salvaging procedures are numerous but relatively inefficient, justifying the need for new therapeutic strategies. In this regard, the recently discovered interleukin (IL)-33 alarmin appears as a possible target. Indeed, IL-33 seems to be specifically released by necrotic cells, and interestingly, is constitutively expressed in human bone, in particular by osteocytes, osteoblasts and marrow adipocytes. Moreover, recent reports suggesting that IL-33 modulates angiogenesis, vascular permeability, osteoclastogenesis and bone resorption, indicate that IL-33 may play a role in ONFH.
Subject(s)
Bone and Bones/physiopathology , Femur Head Necrosis/physiopathology , Interleukins/physiology , Animals , Bone Resorption/physiopathology , Bone Transplantation , Bone and Bones/pathology , Disease Models, Animal , Femur Head Necrosis/diagnosis , Femur Head Necrosis/therapy , Humans , Interleukin-33 , Magnetic Resonance Imaging , Neovascularization, Pathologic/physiopathology , OsteotomyABSTRACT
Distal control of the whey acidic protein (WAP) locus was studied using a transgenic approach. A series of pig genomic fragments encompassing increasing DNA lengths upstream of the mammary specific whey acidic protein (WAP) gene transcription start point (tsp) and 5 kb downstream were used for microinjection in mouse fertilized eggs. Our data pointed out three regions as potent regulators for WAP but not for RAMP3 gene expression (a non mammary-specific gene located 30 kb upstream of the WAP gene). WAP gene activating elements were present in the -80 kb to -30 kb and -145 kb to -130 kb regions whereas inhibitors were present in the -130 kb to -80 kb region. The stimulatory regions were characterized by peaks of histone H4 acetylation and a poor nucleosome occupancy in lactating sow mammary glands but not in liver. These data reveal for the first time the existence of several remote potent regulatory regions of the pig WAP gene.
