Estrogenic status influences nitric oxide-regulated TNF-α release from human peripheral blood monocytes

Summary:

Cytokines and nitric oxide (NO) have been implicated in bone loss caused by estrogen deficiency. Here we evaluated the effect of nitric oxide synthase (NOS) inhibitors on the bone particle resorbing activity and TNF-α release of cultured peripheral blood monocytes (PBM) obtained from 10 premenopausal (PreM) and 10 postmenopausal (PostM) women. Gonadal status (menopause < 3 yr) was assessed by FSH and estradiol. Bone alkaline phosphatase and N-Telopeptide were significantly increased in PostM. Significant differences between PreM and PostM women were observed in bone mineral density of lumbar spine. The bone particle resorbing activity of PBM cultured in the presence of L-arginine-methyl ester (NAME) or aminoguanidine, NOS inhibitors, was determined by ⁴⁵Ca release from rat bone labeled particles. TNF-α release was assayed in supernatants by ELISA. ⁴⁵Ca release was higher in PostM (p < 0.01) and was enhanced by NAME (p < 0.02). Furthermore, TNF-α release from PBM was significantly higher in PostM (p < 0.01). Aminoguanidine significantly increased TNF-α release in PreM. Based on these findings and on the evidence that estrogen stimulates NOS, we suggest that estrogen withdrawal may reduce the inhibitory effect of NO on TNF-α release. Thus, this increased production of TNF-α could contribute to the increased postmenopausal bone turnover.

Nitric oxide - estrogens - osteoporosis - TNF-α - monocytes

References

• 1 Amin A R, Attur M, Vyas P. et al. . Expression of nitric oxide synthase in human peripheral blood mononuclear cells and neutrophils.  J Inflam. 47 190-205 1996; 
• 2 Armour K E, Ralston S H. Estrogen upregulates endothelial constitutive nitric oxide synthase experssion in human osteoblast-like cells.  Endocrinology. 139 799-802 1998; 
• 3 Brandi M L, Hukkanen M, Umeda Z. et al. . Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms.  Proc Natl Acad Sci USA. 92 2954-2958 1995; 
• 4 Calvo M S, Eyre D R, Gundberg C M. Molecular basis and clinical application of biological markers of bone turnover.  Endocr Rev. 17 333-368 1996; 
• 5 Cohen-Solal M E, Boitte F, Bernard-Poenaru O. et al . Increased bone resorbing activity of peripheral monocyte culture supernatants in elderly women.  J Clin Endocrinol Metab. 83 1687-1690 1998; 
• 6 Cohen-Solal M E, Graulet A M, Denne M A, Gueris J, Baylink D, De Vernejoul M C. Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines.  J Clin Endocrinol Metab. 77 1648-1653 1993; 
• 7 Collin Osdoby P, Nickols G A, Osdoby P. 1995 Bone cells function, regulation and communication: a role for nitric oxide.  J Cell Biochem. 57 399-408 1995; 
• 8 Dunstan C R. Osteoprotegerin and osteoprotegerin ligand mediate the local regulation of bone resorption.  The Endocrinologist. 10 18-26 2000; 
• 9 Evans D M, Ralston S H. Nitric oxide and bone.  J Bone Miner Res. 11 300-305 1996; 
• 10 Fox S W, Chow J MW. Nitric oxide synthase expression in bone cells.  Bone. 23 1-6 1998; 
• 11 Furuke K, Burd P R, Horvath-Arcidiacono J A, Hori K, Mostowski H, Bloom E T. Human NK cells express endothelial nitric oxide synthase, and nitric oxide protects them from activation-induced cell death by regulating expression of TNF-alpha.  J Immunol. 163 1473-1480 1999; 
• 12 Jamal S A, Browner W S, Bauer D C, Cummings S R. Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures.  J Bone Miner Res. 13 1755-1759 1998; 
• 13 Jilka R L. Cytokines, bone remodelling, and estrogen deficiency: a 1998 update.  Bone. 23 75-81 1998; 
• 14 Kasten T P, Collin-Osdoby P, Patel N. et al. . Potentiation of osteoclast bone resorption activity by inhibition of nitric oxide synthase.  Proc Natl Acad Sci USA. 91 3569-3573 1994; 
• 15 Leung D YM, Key L, Steinberg J J. et al . Increased in vitro bone resorption by monocytes in the hyperimmunoglobulin E syndrome.  J Immunol. 140 84-88 1988; 
• 16 Löwik C W, Nibbering P H, Van Der Ruit M, Papapoulos S E. Inducible production of nitric oxide in osteoblast like cells and in fetal bone explants is associated with suppression of osteoclastic bone resorption.  J Clin Invest. 93 1465-1472 1994; 
• 17 Manolagas S, Jilka R. Bone marrow, cytokines and bone remodelling. Emerging insights into the pathophysiology of osteoporosis.  N Engl J Med. 332 305-311 1995; 
• 18 McIntyre I, Zaidi M, Towhidul Alam A SM. et al . Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP.  Proc Natl Acad Sci USA. 88 2936-2940 1991; 
• 19 Meldrum D R, Shames B D, Meng X. et al . Nitric oxide downregulates lung macrophages inflammatory cytokine production.  Ann Thorac Surg. 66 313-317 1998; 
• 20 Moncada S, Higgs A. The L-arginine-nitric oxide pathway.  N Engl J Med. 329 2002-2012 1993; 
• 21 Nilas L, Christiansen C. Bone mass and its relationship to age and the menopause.  J Clin Endocrinol Metab. 65 697-702 1987; 
• 22 Ralston S H, Grabowski P S. Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine monophosphate, and prostaglandins.  Bone. 19 28-33 1996; 
• 23 Ralston S H, Ho L P, Helfrich M H, Grabowski P S, Johnston P W, Benjamin N. Nitric oxide: a cytokine-induced regulator of bone resorption.  J Bone Miner Res. 10 1040-1049 1995; 
• 24 Riggs B L, Khosla S, Melton III L J. A unitary model for involutional osteoporosis: Estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men.  J Bone Miner Res. 13 763-773 1998; 
• 25 Riggs B L, Melton L J. Medical progress series: involutional osteoporosis.  N Engl J Med. 314 1676-1686 1986; 
• 26 Sinha B, Eigler A, Baumann K H, Greten T F, Moeller J, Endres S. Nitric oxide downregulates tumor necrosis factor mRNA in RAW 264.7 cells.  Res Immunol. 149 139-150 1998; 
• 27 Turner R T, Riggs B L, Spelsberg T C. Skeletal effects of estrogen.  Endocr Rev. 15 275-300 1994; 
• 28 Van't Hof R, Ralston S. Cytokine induced nitric oxide inhibits bone resorption by inducing apoptosis of osteoclast progenitors and suppressing osteoclast activity.  J Bone Miner Res. 12 1797-1804 1997; 
• 29 Xu P, Morales J A, Muniyappa R, Skafar D F, Ram J L, Sowers J R. Interleukin-1 beta-induced nitric oxide production in rat aortic endothelial cells: inhibition by estradiol in normal and high glucose cultures.  Life Sci. 64 2451-2462 1999; 
• 30 Zancan V, Santagati S, Bolego C, Vegeto A, Puglisi L. 17 β-estradiol decreases nitric oxide synthase II synthesis in vascular smooth muscle cells.  Endocrinology. 140 2004-2009 1999;