Periostin (gene

No abstract

Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn −/− and Postn +/+ mice to intermittent PTH. Compared with Postn +/+ , Postn −/− mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn −/− mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn −/− mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn −/− mice. In addition, primary osteoblasts from Postn −/− mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn −/− osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.

Periostin is a highly conserved matricellular protein that shares close homology with the insect cell adhesion molecule fasciclin 1. Periostin is expressed in a broad range of tissues including the skeleton, where it serves both as a structural molecule of the bone matrix and a signaling molecule through integrin receptors and Wnt-beta-catenin pathways whereby it stimulates osteoblast functions and bone formation. The development of periostin null mice has allowed to elucidate the crucial role of periostin on dentinogenesis and osteogenesis, as well as on the skeletal response to mechanical loading and parathyroid hormone. The use of circulating periostin as a potential clinical biomarker has been explored in different non skeletal conditions. These include cancers and more specifically in the metastasis process, respiratory diseases such as asthma, kidney failure, renal injury and cardiac infarction. In postmenopausal osteoporosis, serum levels have been shown to predict the risk of fracture-more specifically non-vertebral- independently of bone mineral density. Because of its preferential localization in cortical bone and periosteal tissue, it can be speculated that serum periostin may be a marker of cortical bone metabolism, although additional studies are clearly needed.

As they age, mice deficient for the b2-adrenergic receptor (Adrb2 À/À ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of b1-adrenergic receptor signaling and its interaction with b2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for b1-adrenergic receptors and/or b2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2 À/À and wild-type (WT) mice, but not in Adrb1 À/À nor in Adrb1b2 À/À mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2 À/À mice, whereas in Adrb1 À/À and Adrb1b2 À/À double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2 À/À mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the b-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-kB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2 À/À mice. Altogether, these results demonstrate that b1-and b2-adrenergic signaling exert opposite effects on bone, with b1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas b2-adrenergic receptor signaling mainly regulates bone resorption during aging. ß