Constitutively Active Parathyroid Hormone Receptor Signaling in Cells in Osteoblastic Lineage Suppresses Mechanical Unloading-induced Bone Resorption

Abstract

Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor (caPPR), whose expression was regulated by the osteoblastspecific Col1a1 promoter (Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic (Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 (MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity.Bone mass is strictly maintained through dynamic equilibrium of bone formation and bone resorption under the control of various signals including hormones, cytokines, and mechanical stimuli (1). Combined actions of these multiple signals regulate osteoblasts and osteoclasts responsible for bone formation and bone resorption, respectively. Dysregulation of the balance of bone formation and bone resorption leads to pathological bone loss and results in osteoporosis (2).Mechanical loading exerts anabolic action on bone and is essential for the integrity of the bone architecture. Loss of mechanical loading (unloading) results in rapid bone loss caused by enhanced bone resorption and simultaneous suppression of bone formation as seen in disuse osteoporosis (3-8). Mechanisms underlying this catabolic balance of bone metabolism are largely unknown. Although inhibitors for bone resorption have been used clinically, they still fail to fully restore bone mass in patients with severe osteoporosis. Hind limb unloading, in which mice are subjected to tail suspension, results in bone loss and is widely used as a model of disuse osteoporosis. In these animal models, inhibitors for bone resorption such ...

MURF1 deficiency suppresses unloading-induced effects on osteoblasts and osteoclasts to lead to bone loss

“…There were no significant changes in body weight in any of the groups during the course of the study. This confirmed that stress could be considered minimal in our experiments as previously described [Ishijima et al, 2001;Ono et al, 2007;Mizoguchi et al, 2008].…”

“…WT and MURF1 deficient mice were randomized regarding body weight into two groups. The two groups were subjected either to hind limb unloading (HU) or normal housing (loading) (NL) [Ishijima et al, 2001;Ono et al, 2007;Mizoguchi et al, 2008]. Mice were housed for at least 1 week prior to the study.…”

“…HU was conducted by applying a tape to the surface of the hind limb to set a metal clip [Ishijima et al, 2001;Ono et al, 2007;Mizoguchi et al, 2008]. The other end of the clip was fixed to an overhead bar.…”

Angiotensin II Type 2 Receptor Blockade Increases Bone Mass

“…bone formation and bone resorption. Systemic signals such as parathyroid hormone (PTH) 3 and vitamin D are the major regulators of the maintenance of bone mass and blood calcium (1)(2)(3). In addition, bone mass levels are also determined by a central nervous control through the activities of sympathetic tone on both bone formation and resorption sides (4 -7).…”

Disuse osteoporosis: A better understanding of pathophysiology may lead to potential therapies

“…PTH and osteocalcin concentrations are higher post-hibernation relative to prehibernation raising the possibility that anabolic actions of PTH may be important in maintenance of bone mineral content during hibernation [19]. Constitutive activation of PTH/PTHrP receptor signalling in osteoblasts, an action likely to mimic PTH administration, suppresses unloadinginduced bone loss in Col1a1-caPPR transgenic mice [20]. The anabolic effect of PTH on bone may in part relate to PTH mediated down-regulation of sclerostin expression by osteocytes [21].…”