Age-dependent stimulation or inhibition of calcium release from bone cultures by interleukin-1 beta.

Previous studies have shown that interleukin-1 beta (IL-1 beta) is a potent bone resorption stimulating agent in cultures of fetal or neonatal bones. In the present study, evidence has been provided showing that this cytokine failed to stimulate bone resorption in cultured 75-day-old mouse calvaria maintained in a chemically defined medium for 14 days, as determined by measuring calcium release into the medium and histological examination of cultured bones. Moreover, the cytokine significantly inhibited basal bone resorption in cultured 75-day-old mouse calvaria, a finding reminiscent of the paradoxical effect observed with 1 alpha,25-dihydroxycholecalciferol. Since IL-1 beta did not alter the number of osteoclasts present in the cultured older calvaria as compared to the untreated control, we hypothesized that in such cultured older bones the cytokine affects primarily the function rather than proliferation/differentiation of osteoclasts, either directly or indirectly through its action on other cells in bone tissue, such as osteoblasts or stromal cells. Also, it is possible that the cytokine affects the formation and/or function of macrophages that have been shown to participate in the bone resorption process. These findings support the concept that at different stages of host maturation, bone tissue may exhibit a different response to the same osteotropic agent.

Effects of NSAIDs on beagle crevicular cyclooxygenase metabolites and periodontal bone loss.

This investigation focuses on the changes in the concentrations of cyclooxygenase (CO) products present within the crevicular fluid in naturally-progressing periodontitis in the beagle and the effects of various non-steroidal anti-inflammatory drugs (NSAIDs) on these metabolite levels and disease progression. Six groups of 5-6 beagles with periodontitis were followed for 6 months to determine the pretreatment rate of radiographic bone loss. At baseline, groups of animals were placed on soft chow to promote disease progression. Groups were treated with either placebo, three different formulations of systemic ibuprofen, systemic naproxen or topical flurbiprofen. During the 6-month treatment phase, crevicular fluid (CF) samples and radiographs were taken at regular intervals. Radioimmunoassay of CF samples from untreated animals demonstrated a steady increase in prostaglandin E2 (PGE2) over baseline values. At 1 month, CF-PGE2 levels increased 2-fold over baseline and, by 6 months, had reached a 5- to 6-fold elevation. Crevicular fluid thromboxane B2 (CF-TxB2) levels rapidly reached a 4- to 5-fold peak over baseline at 1 month and subsequently dropped to a 2-fold elevation for the remainder of the study. The rate of bone loss (BLOSS) in untreated animals increased 38% during the 6-month period, as compared to baseline pretreatment BLOSS rates. Overall, there was a significant depression in the CF levels of both PGE2 and TxB2 in all NSAID-treated groups. All NSAID treatments significantly retarded BLOSS, ranging from 21.0-36.9% of the control BLOSS rate. Furthermore, CO activation represents a major regulatory step in bone destruction and may thereby serve as an important site for pharmacological modulation.

Inhibition of alveolar bone loss in beagles with the NSAID naproxen.

The non-steroidal anti-inflammatory drug(NSAID) naproxen was studied in 11 beagle dogs over a 13-month period to determine its effect on the progression of periodontitis. Following a 6-month pretreatment period, 5 dogs received naproxen daily at a dosage of 2.0 mg/kg for 1 month, then 0.2 mg/kg for 6 months. Six control dogs received a gelatin capsule daily as placebo. Standardized radiographs were used to measure the rate of bone loss during the pretreatment and treatment periods. In the control dogs, the rate of bone loss was seen to increase during the treatment period although the increase was not statistically significant. In dogs treated daily with naproxen, the rate of bone loss in the treatment period was significantly less at 4 months of treatment; however, at 7 months the difference, though lower than pretreatment rate, was not significant. When the percent change in rate of bone loss during the overall 7-month treatment period was compared with pretreatment rate, the control dogs demonstrated a 38% increase in rate of bone loss during the treatment period contrasting with a 61% decrease in bone loss rate in naproxen-treated dogs. The data indicate that the non-steroidal anti-inflammatory drug naproxen can significantly inhibit alveolar bone loss in beagles. At 4 months of treatment the rate of bone loss in the naproxen-treated dogs was significantly less than pretreatment, but at 7 months of treatment the rate was no longer statistically significantly less than baseline. This probably reflects a dose response to naproxen treatment for, after 30 days of the treatment period, the naproxen dosage was reduced 10-fold due to tolerance by the beagle.

Calcium 'homeostatic' effect of 1 alpha,25-dihydroxycholecalciferol on young adult mouse calvaria in organ culture.

The effect of 1 alpha,25-dihydroxycholecalciferol on calcium release from cultured young adult (75-day-old) mouse calvaria in the presence of indomethacin or dexamethasone was studied. Indomethacin (2.8 x 10(-7) M) or dexamethasone (10(-8) M) abolished or considerably inhibited basal calcium release. At 2.6 x 10(-7) M, 1 alpha,25-dihydroxycholecalciferol prevented the effect of either indomethacin or dexamethasone, resulting in higher calcium release levels approximating those observed in cultures containing only 1 alpha,25-dihydroxycholecalciferol. We have shown previously that in contrast to its effect on neonatal mouse calvaria in culture, 1 alpha,dihydroxycholecalciferol either failed to enhance or even inhibited basal calcium release from cultured 75-day-old mouse calvaria. Furthermore, 1 alpha,25-dihydroxycholecalciferol inhibited PTH- or PGE2-enhanced calcium release from such cultures. These studies demonstrated that, at the same concentration, 1 alpha,25-dihydroxycholecalciferol decreases high calcium release due to various bone resorption-stimulating factors and increases low calcium release values due to various bone resorption-inhibiting factors. This suggested that this vitamin D3 metabolite directly regulates the degree of bone resorption at the bone tissue level resulting in a local calcium 'homeostasis'.

H(+)-stimulated release of prostaglandin E2 and cyclic adenosine 3',5'-monophosphoric acid and their relationship to bone resorption in neonatal mouse calvaria cultures.

The addition of protons to the medium of neonatal mouse calvaria cultures stimulated bone resorption and release of calcium into the medium. In addition, added protons significantly increased the release of prostaglandin E2 (PGE2) and cyclic adenosine 3',5'-monophosphoric acid (cAMP) from the bones. Indomethacin significantly inhibited the release of calcium, PGE2 and cAMP from proton-treated cultures. The positive control, parathyroid hormone (PTH)-treated cultures, also gave rise to bone resorption and calcium release into the medium. However, unlike the addition of protons, the addition of PTH did not stimulate PGE2 release nor did indomethacin inhibit calcium release from PTH-treated cultures. In addition, indomethacin only slightly inhibited cAMP release from PTH-treated cultures, as compared to the marked inhibition by indomethacin of cAMP release from proton-treated cultures. These findings indicate that bone resorption due to added protons is dependent on both PGE2 and cAMP production, whereas bone resorption due to PTH only involves cAMP production.

Age-dependent stimulation or inhibition of calcium release from bone cultures by 1 alpha, 25-dihydroxyvitamin D3.

The effect of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) on calcium release from neonatal and young adult mouse calvaria in tissue culture was studied. At concentrations from 2.6 X 10(-6) M to 2.6 X 10(-9) M, 1 alpha 25-(OH)2D3 enhanced calcium release from 5-day-old calvaria. At the same concentrations, 1 alpha, 25-(OH)2D3 either inhibited or failed to enhance calcium release from 75-day-old calvaria. Parathyroid hormone-enhanced calcium release from 75-day-old calvaria was inhibited considerably by 1 alpha, 25-(OH)2D3 at 2.6 X 10(-6) M and 2.6 X 10(-7) M. These findings suggest that cells involved in the bone resorption process may respond differently to the same stimulus at different stages in the development of the organism. This direct inhibitory effect of 1 alpha, 25-(OH)2D3 on bone resorption in cultured calvaria of older animals may explain, in part, its beneficial effect in the treatment of osteoporosis.

Altering the progression of human alveolar bone loss with the non-steroidal anti-inflammatory drug flurbiprofen.

The treatment of human periodontal diseases relies on mechanical and antimicrobial suppression of the etiologic bacteria. The ability to alter the progression of periodontitis by additionally blocking host pathways involved in the destructive process is an area of current research. Prostaglandins and other metabolites of arachidonic acid are believed to be important host mediators of the bone resorption of diseases such as periodontitis. We have previously examined the effect of inhibitors of prostaglandin production, non-steroidal anti-inflammatory drugs (NSAIDs), on inhibiting alveolar bone loss in beagles. The present study was designed to examine the effect of the NSAID, flurbiprofen, on slowing the radiographic loss of alveolar bone in the human. Fifty-six individuals with radiographic evidence of alveolar bone loss were recruited for study. Forty-four patients remained in the study for the data analysis of loss of alveolar bone. Following a 6 month baseline pretreatment period to measure the radiographic progression of bone loss, half of the patients were administered flurbiprofen, 50 mg. b.i.d., while half were administered a placebo. All patients received a subgingival scaling and pumice by a hygienist every 6 months. The rate of alveolar bone loss in a 2 year treatment period was compared to the baseline 6 month pretreatment period within and between patient groups. Throughout the study, teeth exhibiting obvious loss of bone were exited from study and treated with conventional mechanical therapy. At the end of the pretreatment period both patient groups had a similar mean rate of alveolar bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Advances in diagnosis and detection of oral diseases.

Medicine, particularly with respect to diagnostic decision-making, has seen remarkable advances in the last ten years. The art of diagnosis has become much more of a science. Basic science advances have moved from the laboratory into the hospital and radically changed the way a medical diagnosis is arrived at or confirmed. Dentistry, especially oral diagnosis, as yet has not been a significant part of this general medical advance. However, several examples demonstrate that this situation is starting to change. Oral conditions are beginning to be evaluated with greater precision and sophistication. This report reviews some recent advances in oral diagnostic research and suggests where they will carry dentistry over the next 25 years.

Inhibition of A23187-stimulated bone resorption in tissue culture by serum and indomethacin.

The present study addresses the controversy that currently exists concerning the effect of the divalent cation ionophore A23187 on bone resorption in tissue culture. We show here that this compound is ineffective if serum is present in the culture medium. However, in a serum-free medium it effectively stimulates bone resorption in neonatal mouse calvaria cultures. This finding does account for the various conflicting reports in the literature. Furthermore, the stimulation of bone resorption by the ionophore was accompanied by increased prostaglandin E2 production. Indomethacin inhibited both phenomena, indicating that prostaglandin E2 biosynthesis is involved in mediating the bone resorption-stimulating effect of A23187.