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Home  > Press Release  > “Sympathetic control of bone mass regulated by osteopontin”

“Sympathetic control of bone mass regulated by osteopontin”

Masaki Noda
Professor, Department of Molecular Pharmacology,
Medical Research Institute (right)

Yoichi Ezura
Associate Professor,
Department of Molecular Pharmacology,
Medical Research Institute (left)


Points

1) Molecules linking osteoporosis and nervous system have not been well understood. Our studies identified Osteopontin (OPN) to be this functional linker.
2)Osteoporosis proceeds in bedridden patients and agravity situation. However, molecular mechanisms were largely unknown. Our discover of OPN function will shed lights on the pathophysiology underlying this disease situation.
3) OPN would be a target molecule to contemplate new therapeutics and development of drugs.

Background

Bone formation and bone resorption require a tight regulation of the two facets of bone metabolism, new bone deposition by osteoblasts and bone resorption by osteoclast cells. Pathologic bone loss and bone accumulation disorders are nearly always caused by dysregulation of this balance, either towards bone accumulation (e.g., osteopetrosis) or bone loss (e.g., osteopenia or osteoporosis). The most common disorder of bone loss, osteoporosis, contributes to a high fracture risk and challenges quality of life and longevity of affected populations such as the elderly and post-menopausal women. Osteoporosis can also develop after prolonged inactivity or weightless space travel, due to the loss of mechanical stress stimuli that promote anabolic bone remodeling and inhibit resorption . Unlike bone loss from unloading and inactivity, postmenopausal osteoporosis is characterized by both an increase in bone formation as well as a relatively greater increase in bone resorption, and bone deterioration therefore proceeds more slowly. The primary regulators of bone metabolism include hormones such as parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), inflammatory and anti-inflammatory cytokines and the sympathetic tone of the nervous system, which regulates bone mass through neurotransmitters such as epinephrine and norepinephrine via innervation of bone cells As in the case of disuse (unloading) osteoporosis, bone loss through the symphathetic tone is characterized by stimulation of bone resorption as well as suppression of bone formation. Conversely, inhibition of the sympathetic tone by β-blockers suppresses unloading-induced bone loss by suppressing of bone resorption, as well as enhancing bone formation. Nonetheless, the mechanism by which the sympathetic tone regulates bone catabolism remains largely unknown.
Osteopontin (OPN), a major member of the non-collagenous extra-cellular matrix secreted by osteoblasts and a cytokine involved in proliferation, apoptosis, and inflammatory signaling, has been implicated in bone remodeling after mechanical stress. Indeed, OPN deficient mice show both increased deposition and reduced resorption of bone after unloading. In terms of the control of bone metabolism, the osteopontin knockout phenotype therefore phenocopies treatment with β-blockers. Here, we hypothesize that OPN serves as a molecular link between the sympathetic tone and bone metabolism.

Content of Research

Sympathetic nervous system suppresses bone mass by mechanisms that remain incompletely elucidated. Using cell-based and mice genetics approaches, we show that this activity of the sympathetic nervous system requires osteopontin (OPN), a cytokine and one of the major members of non-collagenous extracellular matrix proteins of bone. Here we found that the stimulation of the sympathetic tone by isoproterenol increased the level of OPN expression in the plasma and bone, and that mice lacking OPN (OPN-KO) suppressed the isoproterenol-induced bone loss by preventing reduced osteoblastic and enhanced osteoclastic activities. In addition we found that OPN is necessary for changes in the expression of genes related to bone resorption and bone formation that are induced by activation of the sympathetic tone. At the cell level, we showed that intracellular OPN modulated the capacity of the β2-adrenergic receptor to generate cAMP with a corresponding modulation of cAMP-response element binding protein (CREB) phosphorylation and associated transcriptional events inside the cell. Our results indicate that OPN plays a critical role in sympathetic tone regulation of bone mass and that this OPN regulation is taking place through modulation of the β2-adrenergic receptor/cAMP signaling system.

Future Potential

New targets of drug and therapeutics could be contemplated based on the fact that OPN is a novel modulator of beta 2 AdR.

Contact

Masaki Noda, MD, PhD
Professor
Dept Molecular Pharmacology, Medical Research Institute
Tokyo Medical and Dental University
MD Tower 24th Floor, Room 2401
5-45 Yushima 1-Chome, Bunkyo-Ku, Tokyo, Japan 113-5810
Tel/Fax 81-3-5803-4061
E-mail: noda.mph(at)mri.tmd.ac.jp

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