Low dose of propranolol down‐modulates bone resorption by inhibiting inflammation and osteoclast differentiation

Abstract

BACKGROUND AND PURPOSEBones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the effects of propranolol in a model of experimental periodontal disease. EXPERIMENTAL APPROACHRats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg -1 propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL-1b, TNF-a and cross-linked carboxyterminal telopeptides of type I collagen (CTX) by ELISA, or intercellular adhesion molecule 1 (ICAM-1), receptor activator of NF-k B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro. RESULTSPropranolol at 0.1 and 5 mg·kg -1 reduced the bone resorption as well as ICAM-1 and RANKL expression. However, only 0.1 mg·kg -1 reduced IL-1b, TNF-a and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate-resistant acid phosphatase (TRAP), cathepsin K and MMP-9. CONCLUSIONS AND IMPLICATIONSLow doses of propranolol suppress bone resorption by inhibiting RANKL-mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters. AbbreviationsAP, arterial pressure; BD, bone density; CTX, cross-linked carboxyterminal telopeptides of type I collagen; DMEM, Dulbecco's modified Eagle medium; DTT, dithiothreitol; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ICAM-1, intercellular adhesion molecule 1; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; NFAT, nuclear factor of activated T cells; OPG, osteoprotegerin; OVX, ovariectomized; RANKL, receptor activator of NF-k B ligand; SaM-1, human periosteum-derived osteoblastic cells; SaOS-2, human osteosarcoma-derived cells; SHR, spontaneous hypertensive rats; TBST, Tris-buffered saline-Tween; TRAP, tartrate-resistant acid phosphatase BJP British Journal of Pharmacology

Effect of combined treatment with zoledronic acid and propranolol on mechanical strength in an rat model of disuse osteoporosis

“…[16][17][18] Rodrigues et al demonstrated that low doses of PRO suppress bone resorption by inhibiting receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis as well as inflammatory markers without affecting hemodynamic parameters. 19 This result is supported by a previous finding, which showed that propranolol stimulates osteoprotegerin (OPG) on its own in osteoblast cells. 20 The ability to stimulate osteoblast, while also damping osteoclasts makes PRO an attractive and unique alternative to antiresorptive therapy for osteoporosis.…”

“…PRO, which could directly prevent bone loss and biomechanical alteration by increasing bone formation and decreasing bone resorption, may be the next anabolic agent for osteoporosis treatment after PTH. 7,8,10,19,20 As immobilization induced bone loss involves both increased bone resorption and decreased bone formation, it seems to be obvious to target the immobilization induced bone loss with a combined antiresorptive and bone anabolic treatment regimen, such as ZOL and PRO. The effects of a combined PRO and ZOL treatment have previously been studied in ovariectomized rats, 7 whereas this treatment regimen has not previously been investigated in immobilization-induced osteopenia.…”

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

“…These molecular findings may explain the lower bone resorption observed in the treated groups, especially at a dose of 10 mg/kg. Interactions between the immune system and bone cells appear to be mediated by inflammatory cells and their related mediators, including cytokines and chemokines, which are able to regulate various inflammatory bone conditions (32,37). In this study, concomitantly with the control of RANKL expression and bone resorption, 15d-PGJ 2 -NC also inhibited leukocyte influx, which had a positive impact on bone resorption prevention.…”

“…The identification of RANKL, its receptor RANK, and the soluble decoy receptor OPG has contributed significantly to the understanding of the skeletal remodeling mechanism involved in the osteoclastogenesis process (29). Considerable efforts are being made to identify drugs able to inhibit RANKL or increase OPG, to adjust the RANKL/OPG ratio in several diseases (30)(31)(32), as well as to develop the use of human OPG constructs, which can powerfully inhibit bone resorption (33,34). More recently, a fully human mAb that binds and inhibits RANKL, called denosumab (AMG 162), was suggested as a promising drug able to reduce biochemical markers of bone resorption (35) in patients with multiple myeloma or bone metastases (36).…”

The β-Adrenergic System and Bone Mineral Remodeling

“…Findings suggest that the pharmacological antagonism of b2 receptors, like genetic ablation studies, cause anabolic effects on bone, which are much more pronounced in situations that favor bone loss, such as gonadectomy, low doses of propranolol or unloading [62,66]. According to the results obtained in b-hydroxylase mouse models, when mice are treated with a non-selective beta blocker, propranolol, they show an increase in bone mass [23,[67][68][69] and improved fracture healing [70]. Baek et al [71] found that using this antagonist attenuates the decline in trabecular mass in mice fed on high-calorie diets.…”