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Potentiation of Osteoclast Bone-Resorption Activity by Inhibition of Nitric Oxide Synthase (Bone Ceil/Nitric Oxide/Aminguanidine) THOMAS P

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Potentiation of Osteoclast Bone-Resorption Activity by Inhibition of Nitric Oxide Synthase (Bone Ceil/Nitric Oxide/Aminguanidine) THOMAS P Proc. Nati. Acad. Sci. USA Vol. 91, pp. 3569-3573, April 1994 Pharmacology Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase (bone ceil/nitric oxide/aminguanidine) THOMAS P. KASTEN*, PATRICIA COLLIN-OSDOBYt, NiRAJ PATELt, PHILIP OSDOBYt, MARILYN KRUKOWSKIt, THOMAS P. MISKO*, STEVEN L. SETTLE*, MARK G. CURRIE*, AND G. ALLEN NICKOLS*t§ *Department of Molecular Pharmacology, Monsanto Corporate Research, St. Louis, MO 63167; tDepartment of Biology and Division of Bone and Mineral Diseases, Washington University, St. Louis, MO 63130; and tDepartment of Pharmacological and Physiological Sciences, St. Louis University Medical School, St. Louis, MO 63104 Communicated by Philip Needleman, December 27, 1993 ABSTRACT We have examined the effects of modulating histochemical level, Schmidt et al. (11) have demonstrated nitric oxide (NO) levels on osteoclast-mediated bone resorption that nitric oxide synthase (NOS) was present in areas ofbone in vitro and the effects ofnitric oxide synthase (NOS) inhibitors coincident with osteoclast and bone-remodeling activity. The on bone mineral density in vivo. Diaphorase-based histochem- report of MacIntyre et al. (12) indicated that NO-generating ical staining for NOS activity of bone sections or highly agents caused a decrease in isolated rat osteoclast cell spread enriched osteoclast cultures suggested that osteoclasts exhibit area and bone resorption. Also, Howard (13) reported that substantial NOS activity that may account for basal NO NO-generating compounds may increase cGMP levels in production. Chicken osteoclasts were cultured for 36 hr on isolated chicken osteoclasts. Furthermore, sodium nitroprus- bovine bone slices in the presence or absence of the NO- side (SNP) has been shown to inhibit the parathyroid hor- generating agent sodium nitroprusside or the NOS inhibitors mone or 1,25-(OH)2-vitamin D3 stimulation of resorption in N-nitro-L-arginine methyl ester and aminoguanidine. Nitro- the 19-day fetal rat limb resorption assay system, with prusside markedly decreased the number of bone pits and the concomitant increases in cGMP (14). average pit area in comparison with control cultures. On the The current study was designed to investigate the role of other hand, NOS inhibition by N-nitro-L-arginine methyl ester NO in both an isolated in vitro avian osteoclast system and or aminoguanidine dramatically increased the number of bone an in vivo rat osteoporosis model system using a NO- pits and the average resorption area per pit. In a model of generating agent and selective NOS inhibitors. These find- osteoporosis, aminoguanidine potentiated the loss of bone ings demonstrate that NO regulates osteoclast bone-resorp- mineral density in ovariectomized rats. Aminoguanidine also tion activity in vitro and in vivo and that similar effects are caused a loss ofbone mineral density in the sham-operated rats. seen in birds and mammals. Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity. These findings MATERIALS AND METHODS suggest that endogenous NO production in osteoclast cultures may regulate resorption activity. The modulation of NOS and Animals. Three-month-old female Sprague-Dawley rats NO levels by cells within the bone microenvironment may be a (250-300 g) from Charles River Breeding Laboratories were sensitive mechanism for local control ofosteoclast bone resorp- used in all in vivo experiments. Pathogen-free White Leghorn tion. fertile eggs were hatched at Washington University. Animal protocols were approved by the institutional Animal Care and Bone-remodeling disorders such as osteoporosis, osteoar- Use Committees. thritis, and periodontal disease are frequently associated with Osteoclast Isolation and Culture. Osteoclasts were isolated perturbations in the interplay between local and systemic from White Leghorn chickens maintained on a low calcium bone-remodeling regulatory pathways. Inflammatory cyto- diet for a period of 4 weeks by the method of Oursler et al. kines and arachidonic acid derivatives have been implicated (15). Osteoclasts were cultured in phenol red-free medium as intercellular messengers involved in humoral-mediated 199 with Earle's salts supplemented with 8.3 mM NaHCO3, and local osteopenia (1, 2). Postmenopausal bone loss asso- 100 mM Hepes (pH 6.8), 1% antibiotic/antimycotic solution ciated with diminished estrogen levels is correlated with (GIBCO) with 5% charcoal-stripped fetal calf serum at 370C increased levels of interleukin 1 and stromal cell-derived in an atmosphere of 95% air/5% CO2. For all cGMP studies, interleukin 6, cytokines known to stimulate osteoclast activ- osteoclasts were cultured at 1-2 x 105 osteoclasts per well in ity and development (3, 4). Estrogen also directly inhibits 24-well tissue culture dishes overnight before SNP addition. osteoclast-mediated resorption (5, 6) and affects other bone For bone-resorption studies, 5 x 104 osteoclasts were plated cells (4, 7). The complexity of signals associated with normal directly onto bovine cortical bone slabs in 48-well tissue and pathological bone remodeling underscores the interac- culture dishes and cultured overnight, modulators of NO tive nature of this tissue. were added, and the resorption assay was stopped after an Bone-degrading osteoclasts arise from cells within the additional 36 hr by fixation in 1% formaldehyde. monocyte-macrophage lineage (8) and, although possessing Diaphorase Staining for NOS Activity. NOS-associated a unique ability to resorb bone, share various characteristics NADPH-dependent diaphorase activity was examined on with macrophages. Macrophages release the cytotoxic short- cultured isolated avian osteoclasts and on frozen sections of lived reactive radical nitric oxide (NO) in response to inflam- matory cytokines and agents (9, 10). Osteoclasts probably Abbreviations: NOS, nitric oxide synthase; NAME, N-nitro-L- make NO and also serve as targets for NO action. At the arginine methyl ester; AG, aminoguanidine; TRAP, tartrate- resistant acid phosphatase; BMD, bone mineral density; SNP, sodium nitroprusside. The publication costs of this article were defrayed in part by page charge §To whom reprint requests should be addressed at: Monsanto payment. This article must therefore be hereby marked "advertisement" Corporate Research, Building T3P, 800 North Lindbergh Boule- in accordance with 18 U.S.C. §1734 solely to indicate this fact. vard, St. Louis, MO 63167. 3569 Downloaded by guest on September 29, 2021 3570 Pharmacology: Kasten et al. Proc. NatL Acad. Sci. USA 91 (1994) avian tibias obtained from animals maintained on a low calcium diet, which were fixed and processed according to Sainte-Marie (16). Isolated osteoclasts were plated onto bovine cortical bone slices or glass coverslips. Cultured osteoclasts were rinsed in Hanks' balanced salt solution, pH 7.2 (HBSS), fixed in 2.5% glutaraldehyde/HBSS, rinsed, air-dried, and stained for NOS activity using the diaphorase staining protocol of Schmidt et al. (11). Staining was done with and without NADPH to determine NADPH-dependent NOS diaphorase activity. cGMP Measurement. Isolated osteoclasts cultured over- night on tissue culture dishes were treated with isobutyl- methylxanthine (1 mM for 10 min) plus or minus SNP. The medium was removed, cGMP was extracted by addition of ice-cold HCl (0.1 M for 10 min), and cGMP concentrations were determined by RIA. Quantitative Pit Resorption Assay. Osteoclasts cultured on bone slices were rinsed in HBSS, fixed in 1% formalin/ HBSS, rinsed, and stained for tartrate-resistant acid phos- phatase (TRAP) (15). The number of TRAP-positive, multi- nucleated cells for each treatment was obtained by exami- nation of eight random fields per slice (two slices per treatment) using a photomask for size, orientation, and reference for each field. After this determination, the cells were removed with 0.01 M NH40H and rubbing, so that the number and area of resorption pits could be quantitated. Dark-field reflective microscopy permitted excellent visual- ization of pits, and all measurements were performed on Ai video-captured images linked to a Leica Quantimet image ..... ..... analysis program. Total area, mean pit area, pits per cells, and percentage of total area resorbed were determined. Bone Mineral Density (BMD) in Normal and Ovariectomized Rats. Female Sprague-Dawley rats were housed individually B and maintained on a 0.4% calcium diet and deionized water throughout the protocol. On day zero, the rats were divided into groups (n = 6 per group), weighed, and anesthetized with FIG. 1. Diaphorase staining of osteoclasts. (A) Photomicrograph xylaxine at 10 mg/kg/ketamine at 50 mg/kg (i.m.). The left of a frozen section of chicken tibia from an animal maintained on a femur and lumbar vertebrae were scanned for BMD by using low calcium diet for 4 weeks. Section was stained for NOS NADPH- a Hologic (Waltham, MA) model QDR-1000 dual energy dependent diaphorase activity. Large intensely stained osteoclasts x-ray absorptiometer. Animals were ovariectomized or (arrowheads) are observed closely associated with bone trabeculae with (b). Lining cells or osteoblasts also exhibit positive staining for NOS sham-operated by externalization ofthe ovaries removal diaphorase activity (arrows). (x290.) (B) Photomicrograph using or examination and replacement. Aminoguanidine (AG) was bright-field reflective light microscopy of isolated osteoclasts cul- administered by continuous infusion (130 mg/kg per day) tured
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