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Osteoclastic bone resorption plays a central role in the joint destruction of rheumatoid arthritis patients. Several bone resorptive cytokines are implied to contribute to the mechanism through induction of RANKL/ODF in synovial cells and/or activated T cells. The target of the RA therapy should be focused on this destructive aspect in relation to the original RA pathophysiology.
As assessed by urine pyridinium cross-links, bone resorption increases at night. This has been ascribed to either the nocturnal rise of serum parathyroid hormone (PTH) or immobilization. ICTP is the carboxyterminal telopeptide region of type I collagen in bone, cross-linked via pyridinium cross-links and liberated during the degradation of type I collagen. To study whether the nocturnal rise in bone resorption is seen also in serum type I collagen carboxyterminal telopeptide (ICTP) and whether this rise is abolished by bedtime calcium or calcitonin, nine healthy postmenopausal women participated in three 24 hour sessions. At 2200 hours, either 1 g of oral calcium or 200 IU of intranasal calcitonin or no treatment (control session) were given. The participants were recumbent from 2200 hours to 0600 hours. Like urinary pyridinolines, serum ICTP showed a clearcut nocturnal rise during the control session, increasing from 3.7 +/- 0.3 micrograms/liter (mean +/- SE) at 2000 hours to 4.9 +/- 0.4 micrograms/liter at 0600 hours (P < 0.001). Administration of calcium did not affect either serum ICTP or urinary pyridinolines, although it decreased serum intact PTH by 18% (P < 0.001) as assessed by areas under curve (AUC) after 2200 hours. Serum ICTP and urinary pyridinolines remained unchanged also after administration of calcitonin which increased the AUC for serum intact PTH by 9% (P < 0.05). In conclusion, serum ICTP follows a circadian rhythm in healthy postmenopausal women. The nocturnal rise in markers of bone resorption is not due to PTH, and its dependency on the function of osteoclasts is open to question.
Production of superoxide radicals by osteoclasts is necessary for normal bone degradation. White blood cell superoxide, needed for bacterial killing, is produced by activated NADPH oxidase. Since osteoclasts and white blood cells share a common hematopoietic origin, we initiated experiments to test the hypothesis that superoxide radicals at the osteoclast-bone interface are produced by NADPH oxidase. Diphenyl iodonium (IDP), an inhibitor of NADPH oxidase, blocked superoxide generation and decreased osteoclastic bone resorption in cultures of calvarial explants from normal mice. Interferon (IFN) gamma, a stimulant of NADPH oxidase activity, increased superoxide production and bone resorption in cultures of calvarial explants from osteopetrotic (microphthalmic) mice. IDP blocked the stimulatory effects of IFN in this bone resorption model. These data suggest that osteoclastic superoxide is produced by NADPH oxidase.
Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.
Our previous study (Y. Kawata, S. Hanazawa, S. Amano, Y. Murakami, T. Matsumoto, K. Nishida, and S. Kitano, Infect. Immun. 62:3012-3016, 1994) showed that Porphyromonas gingivalis fimbriae stimulate bone resorption in vitro. Since it has recently been demonstrated that tyrosine kinase encoded by the c-src gene plays an important role in osteoclastic bone resorption, in the present study we examined the effect of a tyrosine kinase inhibitor on the fimbria-stimulated bone resorption. Genistein, a potent inhibitor of tyrosine kinase, markedly inhibited bone resorption stimulated by the fimbriae. Genistein also inhibited induction of several tyrosine-phosphorylated proteins in the fimbria-treated calvarial bone cells from mouse embryos.
The CD28 costimulation at TCR signaling plays a pivotal role in the regulation of the T cell response. To elucidate the role of T cells in periodontal disease, a system of cell transfer with TCR/CD28-dependent Th1 or Th2 clones was developed in rats. Gingival injection of specific Ag, Actinobacillus actinomycetemcomitans 29-kDa outer membrane protein, and LPS could induce local bone resorption 10 days after the transfer of Ag-specific Th1 clone cells, but not after transfer of Th2 clone cells. Interestingly, the presence of LPS was required not only for the induction of bone resorption but also for Ag-specific IgG2a production. LPS injection elicited the induction of expression of both B7-1 and B7-2 expression on gingival macrophages, which otherwise expressed only MHC class II when animals were injected with Ag alone. The expression of B7 molecules was observed for up to 3 days, which corresponded to the duration of retention of T clone cells in gingival tissues. Either local or systemic administration of CTLA4Ig, a functional antagonist of CD28 binding to B7, could abrogate the bone resorption induced by Th1 clone cells combined with gingival challenge with both Ag and LPS. These results suggest that local Ag-specific activation of Th1-type T cells by B7 costimulation appeared to trigger inflammatory bone resorption, whereas inhibition of B7 expression by CTLA4Ig might be a therapeutic approach for intervention with inflammatory bone resorption.
Interferon-gamma (IFN-gamma) has been shown to inhibit interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) stimulated bone resorption by strongly stimulating nitric oxide (NO) synthesis. Here we studied the mechanisms underlying this inhibition. Osteoclasts were generated in 10-day cocultures of mouse osteoblasts and bone marrow cells and the effect of cytokine-induced NO on osteoclast formation and activity was determined. Stimulation of the cocultures with IL-1 beta, TNF-alpha and IFN-gamma markedly enhanced NO production by 50- to 70-fold, and this was found to be derived predominantly from the osteoblast cell layer. When high levels of NO were induced by cytokines during early stages of the cocultures, osteoclast formation was virtually abolished and bone resorption markedly inhibited. Cytokine stimulation during the latter stages of coculture also resulted in inhibition of bone resorption, but here the effects were mainly due to an inhibitory effect on osteoclast activity. At all stages, however, the inhibitory effects of cytokines on osteoclast formation and activity were blocked by the NO-synthase inhibitor L-NMMA. Further investigations suggested that the NO-mediated inhibition of osteoclast formation was due in part to apoptosis of osteoclast progenitors. Cytokine stimulation during the early stage of the culture caused a large increase in apoptosis of bone marrow cells, and these effects were blocked by L-NMMA and enhanced by NO donors. We found no evidence of apoptosis in osteoclasts exposed to high levels of cytokine-induced NO at any stage in the culture, however, or of apoptosis affecting mature osteoclasts exposed to high levels of NO, suggesting that immature cells in the bone marrow compartment are most sensitive to NO-induced apoptosis. In summary, these studies identify NO as a potentially important osteoblast-osteoclast coupling factor which has potent inhibitory effects on bone resorption. These actions, in turn, are mediated by inhibition of osteoclast formation probably due to NO-induced apoptosis of osteoclast progenitors and by inhibition of the resorptive activity of mature osteoclasts.
IL-6 is a pleiotropic cytokine that plays a critical role in bone resorption. We describe two allelic variants in the IL-6 promoter, -572 and -174 G-->C, that alone and in combination influence IL-6 activity in vitro and in vivo. The association of IL-6 -572 genotypes and -572/-174 G-->C haplotypes with serum C-reactive protein (CRP), serum and urinary C-terminal cross-linking of type I collagen (a marker of bone resorption), and osteocalcin (a marker of bone formation) was investigated in a cohort of healthy postmenopausal women (n = 495; mean age +/- SD, 72 +/- 5.7 yr). Among IL-6 -572 genotypes, CRP was 37% higher (P = 0.02) and urinary C-terminal cross-linking of type I collagen was 20% higher (P = 0.01) in the presence of the C allele, whereas serum osteocalcin was not different. IL-6 -572/-174 haplotypes (G/C, G/G, and C/G) were significantly associated with all biochemical markers, and additive effects of the two polymorphic loci were found. Thus, there was a significant increase in the level of CRP (up to +79%; P = 0.007) and bone resorption markers (up to +32%; P = 0.017) with a decreasing number (from four to one) of IL-6 protective alleles -572G and -174C. In addition, there was a trend for lower age-adjusted bone mineral density at the lumbar spine in subjects with less IL-6 protective alleles (up to -9.6%; P = 0.037; P = 0.08 after further adjustment for weight). In conclusion, we describe two functional polymorphisms in the IL-6 gene regulatory region associated with IL-6 activity in postmenopausal women, both systemically (CRP) and locally in bone. As such, IL-6 polymorphisms are able to influence the risk of osteoporosis as well as other chronic disorders involving IL-6 activity.
OBJECTIVE: We compared an established urine marker (total deoxypyridinoline (DPD), related to creatinine (cr)) with a plasma marker (CTX) to evaluate whether the methods are equally suited to detect increased bone resorption in women after the menopause and to see whether both markers show normal bone resorption in postmenopausal women on hormone replacement therapy (HRT). METHODS: DPD in first morning void urines was measured by an automated HPLC system. CTX ("beta-CrossLaps") was measured on the automated electrochemiluminescence analyzer E170 (Roche Diagnostics, Germany). For CTX, EDTA plasma and serum samples taken from fasting patients in the morning between 08.00 and 08.30 were analyzed. 49 women were premenopausal, 43 women were postmenopausal without HRT, and 13 women were postmenopausal on HRT (mostly on oral medication) for more than six months. RESULTS AND DISCUSSION: Inter-assay coefficients of variation (CVs) at three different concentrations were 6.0%, 6.7% and 7.2% for the assay of DPD and 2.58%, 1.83% and 1.99% for CTX, respectively. CTX was more stable in EDTA plasma than in serum. 21/43 (49%) of postmenopausal women without HRT showed increased DPD/cr ratios and 19/43 (44%) showed elevated CTX concentrations. Regarding postmenopausal women on HRT, DPD/cr ratios were elevated in 3/13 women, whereas plasma CTX showed levels within the premenopausal range in all 13 women. It is discussed that in some cases a lower muscle mass as a result of increasing age or as a result of oral HRT might increase the urinary DPD/cr ratio by lowered excretion of cr. This effect would raise the number of cases with an elevated DPD/cr ratio after the menopause out of proportion. CONCLUSION: CTX is determined with very high precision on the E170. CTX, if measured in EDTA plasma samples from fasting patients in the morning, seems to indicate bone resorption in women on HRT correctly as normal. The DPD/cr ratio in urine of women on HRT is increased in some cases above normal, presumably by lowered excretion of cr. According to our results, plasma (or serum) markers of bone resorption seem to be preferable over cr-related urine markers.
(-)-Menthol, a monoterpene from Mentha species (Lamiaceae), has been shown to inhibit bone resorption in vivo by an unknown mechanism. In the present study, plasma and urine profiling in rats determined by GC/MS demonstrate that (-)-menthol is extensively metabolized, mainly by hydroxylation and carboxylation, and excreted in the urine, in part as glucuronides. In plasma, very low concentrations of (-)-menthol metabolites were detected after a single dose of (-)-menthol, whereas after repeated treatment, several times higher concentrations and long residence times were measured. In contrast, the elimination of unchanged (-)-menthol was increased by repeated treatment. (-)-Menthol, at concentrations found in plasma, did not inhibit bone resorption in cultured mouse calvaria (skull). However, the neutral metabolites of (-)-menthol, extracted from urine of rats fed with (-)-menthol, inhibited bone resorption in vitro, the concentrations being at plasma level or higher. These results suggest that not (-)-menthol itself, but one or several of its neutral metabolites inhibit the bone resorbing cells in vivo.
The collagen metabolites hydroxyproline (HYP), deoxypyridinoline (DPD), and the carboxyterminal telopeptide of type I collagen (ICTP) are suitable markers for bone resorption in humans and several animal species. The purpose of this study was to describe the course of bone resorption markers during short-term hypocalcemia induced with disodium ethylenediaminetetraacetic acid (Na2EDTA) and to investigate whether bone resorption is increased in dairy cows under these conditions. EDTA infusions have been used as a model for periparturient paresis in dairy cows and to estimate the calcium mobilization rate from body reserves in ruminants. In this study, hypocalcemia was induced by means of a 5% Na2EDTA infusion (0.55 mg/kg/min Na2EDTA for 5 h = total dose of 100.6 g). Two experiments were conducted: (1) Six 4-11 years-old Brown Swiss cows were infused intravenously with EDTA for 5 h. Blood and urine samples were taken repeatedly from 1 day before until 10 days after infusion. (2) Towards the end of the lactation, the experiment was repeated with the same animals after a 14-day-period of feeding a low calcium diet (26 g/animal per day). The EDTA-infusion induced hypocalcemia and hypophosphatemia. The HYP-, DPD- and ICTP-concentration remained mainly unaffected during both infusions. Only DPD showed an increase during infusion and HYP an increase 2 days after the infusion. In conclusion, the EDTA infusion had little effect on the concentrations of the measured bone markers, which may be due to the fact that the serum calcium pool was refilled by increased absorption of Ca via the gastrointestinal tract. From these results, it can be concluded that bone resorption was not influenced by EDTA infusion.
We have examined the effect of the micro-opioid analgesic buprenorphine on osteoclastic bone resorption in vitro and in the rat adjuvant arthritis model. In the bone slice assay buprenorphine inhibited osteoclastic bone resorption with an IC50 of 1 microM. This effect was not mimicked by the micro-opioid agonist ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin and was not prevented by the micro-opioid antagonist naloxone. Since other agents that inhibit osteoclastic bone resorption, such as bisphosphonates and calcitonin prevent bone erosion in the rat adjuvant arthritis model, we also examined the effect of buprenorphine in this model. Surprisingly, buprenorphine exacerbated inflammation measured by paw volume and increased joint destruction assessed by X-ray scores, in the injected paws and particularly in the non-injected paws. These studies also show that attempts to ameliorate animal suffering in this chronic model by using centrally acting analgesics such as buprenorphine may lead to complications in interpreting screening results obtained with novel, potential anti-arthritic compounds.
We reported previously that an osteoblast-rich population of mouse calvarial cells treated with lipopolysaccharide produced on interleukin-1 (IL-1)-like cytokine that closely resembles IL-1. In the present study, we examined whether or not the IL-1-like cytokine stimulates bone resorption. As a result we found that the cytokine stimulate bone resorption significantly, and the stimulatory effect was dependent on cytokine dose and length of culture time. The stimulation of bone resorption and IL-1-like cytokine activity appear to be in parallel. Since the stimulatory effect of the cytokine was not abolished in the presence of indomethacin, the cytokine may stimulate bone resorption in a prostaglandin metabolite-independent manner. These results suggest the possibility that the IL-1-like cytokine may be involved as an autoregulatory factor in the bone-remodeling system.
The primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts. Osteoclasts express high levels of the c-Src protein and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have not been elucidated. We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures. In vitro bone resorption by osteoclast-like cells (OCLs) is inhibited by both c-src and c-cbl antisense oligonucleotides. Furthermore, tyrosine phosphorylation of c-Cbl and the localization of c-Cbl-containing structures to the peripheral cytoskeleton are impaired in resorption-deficient c-src- OCLs, as well as in wild-type OCLs that have been treated with c-src antisense oligonucleotides. These results indicate that c-Cbl may act downstream of c-Src in a signalling pathway that is required for bone resorption.
The aim of this study was to evaluate strategies to halt the progression of severe dystrophic calcification in a patient with progressive systemic sclerosis (PSS) and to monitor serial changes in biochemical markers of bone resorption and indices of calcium (Ca) metabolism in response to therapy. The relationship of bone turnover to the extent of dystrophic calcification was also investigated in a number of additional patients with varying degrees of calcinosis. Serial markers of bone turnover and indices of Ca metabolism were measured over a 3-year period in one patient with PSS and severe dystrophic calcification. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA). Bone turnover in this patient and two additional patients with PSS or dermatomyositis (DM) and severe dystrophic calcification (Group A, n = 3) was compared with that in patients with connective tissue disease with little or no evidence of dystrophic calcification (Group B, n = 13). Serial data on one patient with severe progressive calcinosis showed increased bone resorption markers, which remained high over a 3-year period despite antiresorptive therapy. BMD was low. Patients with PSS/DM with severe dystrophic calcification had higher bone resorption than those with minimal or no evidence of calcification. Mean serum ionized Ca and urinary Ca excretion were both lower in those with severe calcinosis. Bone resorption was increased in patients with connective tissue disease and severe dystrophic calcification. Several antiresorptive agents were shown to be ineffective in limiting either bone turnover or clinical progression in one patient.
The supplementation of a low phosphate diet with vitamin D has been shown to result in an increase in bone resorption in the hypophosphataemic rat. The aim of the present study was to determine if administration of vitamin D to rats fed a vitamin D- and phosphate-depleted diet would result in an increase in the circulatory levels of the active vitamin D metabolite 1,25(OH)2D3 and an associated increase in bone resorption. Three groups of weanling Sprague-Dawley rats were used. The first group consisted of control animals on a normal laboratory stock diet and the second and third groups were experimental animals receiving a vitamin D- and phosphate-deficient diet with the third group receiving vitamin D supplementation. All animals were housed in the dark. After 30 days on the diet the experimental animals received 0.1 mmol NaH2PO4 by intraperitoneal injection. Blood was sampled at zero, 3, 6, 18 and 48 h post-injection and analysed for the vitamin D metabolites 25(OH)D3 and 1,25(OH)2D3, calcium and inorganic phosphate (Pi). The serum analyses revealed that the level of 25(OH)D3 in the hypophosphataemic animals was significantly lower than that of the control animals. However, the 1,25(OH)3D3 level was initially significantly higher, then dropped to the control level at 18 h post-intraperitoneal injection of phosphate. Further, the serum levels of 25(OH)D3 and 1,25(OH)2D3, calcium and Pi in the hypophosphataemic animals supplemented with vitamin D were significantly higher than those of the vitamin D-deficient animals. Also the vitamin D-supplemented animals exhibited significantly greater levels of bone resorption. These results therefore, are consistent with a role of 1,25(OH)2D3 in bone resorption in hypophosphataemic rats.
Osteoclastic bone resorption requires the formation of a tightly sealed compartment between the osteoclast and the mineralized bone matrix. This compartment functions as an extracellular "lysosome" which contains proteolytic enzymes and acids. Vitronectin receptors (VnR, integrin alpha v beta 3) displayed on the osteoclast cell surface may play a role in the attachment of osteoclasts to the resorption surface. VnR are known to bind to arginyl-glycyl-aspartyl (RGD)-containing matrix proteins and it has recently been reported that soluble peptides containing RGD sequences can block osteoclast attachment to bone and inhibit bone resorption in vitro. In this study echistatin, a naturally-occurring protein containing an RGD-sequence motif, was shown to completely inhibit osteoclast-mediated bone resorption in vivo. Echistatin or smaller derivative peptides may prove useful in the treatment of disorders characterized by excess bone resorption, such as osteoporosis and metastatic bone disease.
OBJECTIVES: This study measured the response of deoxypyridinoline, a biomarker of bone resorption, during 11 weeks of Marine recruit training. METHODS: Urine samples were obtained from 155 female and 58 male Marine recruits from the first morning void every 3 days during training. Training miles of weight-bearing exercise were recorded daily, and injury data were obtained from the medical clinic staff. RESULTS: Deoxypyridinoline was significantly (p < 0.001) increased at week 2 and weeks 9 through 11 for women and at weeks 10 and 11 for men. The increase in bone resorption corresponded to an increase in miles of weight-bearing exercise performed throughout training. The incidence of stress fracture and reaction was 3.9% and 14.8%, respectively, for women and 1.7% and 3.4%, respectively, for men. CONCLUSIONS: Significant bone resorption took place at the end of Marine recruit training due to accumulation of weight-bearing exercise throughout training and the increase in marching toward the end.