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Biomedical subjects

S E Papapoulos

Publications and source records attributed to S E Papapoulos.

At least 19 recordsLinked to original sources
PubMed2005

Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis.

In a recent multinational, double-blind, placebo-controlled, randomized, phase III study (BONE: IBandronate Osteoporosis Vertebral Fracture trial in North America and Europe), oral daily ibandronate (2.5 mg) significantly and substantially reduced the risk of new vertebral fractures by 62% relative to placebo after 3 years of treatment. The objective of the present study was to retrospectively analyze data from the BONE study to examine the efficacy of oral ibandronate in preventing incident vertebral fractures of greater severity. This analysis was conducted on the placebo and oral daily ibandronate (2.5 mg) arms of the BONE study, comprising a total of 1964 women (aged 55-80 years, >or=5 years postmenopause) with osteoporosis. Vertebral fractures on annual lateral radiographs of the spine were graded as mild, moderate, or severe, using criteria derived from an established semiquantitative technique. The findings demonstrate that in addition to being effective in significantly reducing the risk of new vertebral fractures of all severities, oral daily ibandronate has a pronounced effect on the more severe, most clinically relevant, vertebral fractures: a significant and sustained reduction of 59% in the relative risk of combined new moderate and severe vertebral fractures was observed at years 1 (P = 0.0164), 2 (P = 0.0004), and 3 (P < 0.0001).

Administration, Oral↗
PubMed2005

Bone morphogenetic proteins and their antagonists: the sclerostin paradigm.

Sclerosteosis and Van Buchem disease are two closely related sclerosing disorders, characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is due to premature termination mutations in the SOST gene, whereas Van Buchem disease has been associated with a 52 kb deletion downstream of the SOST gene that most likely inhibits SOST gene transcription. The gene product, sclerostin, is an osteocyte-expressed negative regulator of bone formation with amino acid sequence similarity with the DAN family of secreted glycoproteins, that share the capacity to antagonize bone morphogenetic protein (BMP) activity. The exact mechanism, however, by which sclerostin inhibits osteoblastic bone formation is still uncertain. While it binds BMPs and antagonizes their bone forming capacity, it cannot antagonize all BMP responses. Sclerostin's mechanism of action is, therefore, distinct from that described for classical BMP antagonists. The restricted expression of sclerostin and the exclusive bone phenotype of good quality of patients with sclerosteosis or Van Buchem disease provide the basis for the development of therapeutics that stimulate bone formation, such as, for example, an antibody against sclerostin.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations.

OBJECTIVE: To estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype-phenotype associations. METHODS: We performed a case-control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed. RESULTS: Five percent of patients had at least 1 first-degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3-75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin-associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease. CONCLUSION: Our data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates.

Bisphosphonates (BPS) inhibit bone resorption and are divided into two classes according to their chemical structure and mechanism of action: nonnitrogen containing BPS such as etidronate and clodronate that are of low potency and inhibit osteoclast function via metabolism into toxic ATP-metabolites and nitrogen-containing BPS (NBPS), such as alendronate and risedronate that inhibit the enzyme of the mevalonate biosynthetic pathway farnesyl pyrophosphate synthase (FPPS), resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton. Previously, studies in various cell types suggested, however, that pamidronate functions by mechanism(s) additional or independent of the mevalonate pathway. To examine if such mechanism(s) are also involved in the action of NBPS on osteoclastic bone resorption, we examined the action of alkyl and heterocyclic NBPS with close structural homology on FPPS/isopentenyl pyrophosphate isomerase (IPPI) activity, on osteoclastic resorption, and on reversibility of this effect with GGOH. As expected, both pamidronate and alendronate suppressed bone resorption and FPPS/IPPI activity, the latter with greater potency than the first. Surprisingly, however, unlike alendronate, the antiresorptive effect of pamidronate was only partially reversible with GGOH, indicating the involvement of mechanism(s) of action additional to that of suppression of FPPS. Comparable results were obtained with the heterocyclic NBP NE-21650, a structural analog of risedronate. Thus, despite an effect on FPPS, the actions on bone resorption of some NBPS may involve mechanisms additional to suppression of FPPS. These findings may lead to identification of additional pathways that are important for bone resorption and may help to differentiate among members of the NBP class which are currently distinguished only according to their potency to inhibit bone resorption.

Animals↗
PubMed2003

Ibandronate: a potent new bisphosphonate in the management of postmenopausal osteoporosis.

Osteoporosis is a serious, common skeletal disease. Oral bisphosphonates are among the most effective therapeutics available to manage this condition. Currently, bisphosphonates are administered orally either daily or once weekly. Less frequent dosing, while retaining efficacy, may provide greater convenience, thereby promoting long-term adherence to treatment and maximising therapeutic outcomes. Ibandronate is a highly potent nitrogen-containing bisphosphonate that has been given orally or intravenously at variable dosing intervals for the prevention and treatment of osteoporosis. Recent studies with oral ibandronate, given daily or intermittently with a between-dose interval longer than two months to women with postmenopausal osteoporosis, demonstrated significant and sustained antifracture efficacy. Additional studies showed that ibandronate given as a convenient intravenous injection every three months induces significant increases in bone mineral density and suppression of bone turnover. Ongoing studies aim to determine the optimal therapeutic regimen of this promising new bisphosphonate in clinical practice.

Administration, Oral↗
PubMed2002

Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors.

Nitrogen-containing bisphosphonates (NBps) are taken up by osteoclasts and inhibit farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway. There is evidence, however, that cells other than mature osteoclasts, like osteoclast precursors and osteoblasts, are also involved in the action of Bps on bone resorption in vitro. To examine this issue further, we developed a new in vitro model, which allows the study of the effects of additives on early osteoclast precursors. In this model, osteogenic cells are essential for osteoclastogenesis. The model consists of 15-day-old fetal mouse metatarsals. At time of explantation, these bone rudiments do not yet contain a mineralized matrix or osteoclasts; only early osteoclast precursors are present in the perichondrium. During culture and after the addition of Nabeta-glycerolphosphate, the bones form a mineralized matrix that is consequently resorbed by osteoclasts that develop from their precursors. Short treatment of these explants with Bps, before the formation of a mineralized matrix, resulted in a subsequent dose-dependent inhibition of bone resorption. The relative potencies of eight Bps to suppress resorption were comparable with those observed after the addition of Bps after the formation of a mineralized matrix, the natural target of Bps. In addition, the effects of the NBp olpadronate, but not of clodronate, on osteoclastic resorption, could be partly reversed by geranylgeraniol. Results indicate that Bps can suppress osteoclastic resorption in vitro by a direct action on very early osteoclast precursors at the bone surface, and not by affecting the osteoclastogenic capacity of osteogenic cells. Moreover, the mechanism of action of the NBp olpadronate, but not clodronate, on early tartrate-resistant acid phosphatase-negative osteoclast precursors involves inhibition of protein geranylgeranylation, indicating a molecular mechanism similar to that established for mature osteoclasts.

Animals↗
PubMed2002

A potential role for the mast cell in the pathogenesis of idiopathic osteoporosis in men.

Osteoporosis is increasingly being recognized in men. Secondary causes are often implicated, but the mechanism of bone loss remains unclear in about a third of patients. The mast cell is a complex cell that stores a number of factors known to affect bone metabolism. Patients with systemic mastocytosis often demonstrate osteoporosis and bone marrow mast cells may be increased in osteoporotic postmenopausal women. We address the possible role of the mast cell in the pathophysiology of male osteoporosis by studying the relationship between bone marrow infiltration with mast cells and the 24 h urine excretion of N-methylhistamine, and the severity of osteoporosis in 48 consecutive men with idiopathic osteoporosis (bone mineral density Z score of <-1 and/or at least one prevalent vertebral fracture). Secondary causes for osteoporosis were excluded and none of the patients had systemic manifestations of enhanced mast cell activity. A widely variable number of morphologically normal mast cells were counted in toluidine blue-stained sections from 42 of 46 evaluable bone marrow biopsies. In 4 of the 42 biopsies (9%), clusters of abnormal mast cells were identified. These four patients were the only ones who also demonstrated increased 24 h urine excretion of N-methylhistamine. There was a significant positive relationship between mast cell number and the 24 h urine excretion of N-methylhistamine reflecting mast cell activity (p = 0.0001), and this latter measurement correlated negatively with bone mineral density (BMD) at the lumbar spine (p < 0.001). We identified clinically important bone marrow cell infiltration with pathologic mast cells in the absence of systemic manifestations of mast cell hyperactivity as an additional secondary cause for osteoporosis in some 9% of men with idiopathic osteoporosis, and found urinary excretion of N-methylhistamine to be above the upper limit of the normal laboratory reference range diagnostic for this cause of secondary osteoporosis. The more continuous spectrum in the relationship between mast cell activity and BMD supports a potential role for this cell in the pathogenesis of idiopathic male osteoporosis.

Adult↗
PubMed2002

Interleukin 17 synergises with tumour necrosis factor alpha to induce cartilage destruction in vitro.

BACKGROUND: Interleukin 17 (IL17) is produced by activated T cells and has been implicated in the development of bone lesions and cartilage degradation in rheumatoid arthritis (RA). OBJECTIVE: To determine whether IL17, alone or together with tumour necrosis factor alpha (TNFalpha), induces cartilage destruction in vitro. METHODS: Fetal mouse metatarsals stripped of endogenous osteoclast precursors were used to study the effect of IL17 on cartilage degradation independently of osteoclastic resorption. Cartilage destruction was analysed histologically by Alcian blue staining. RESULTS: IL17 alone, up to 100 ng/ml, had no effect on the cartilage of fetal mouse metatarsals. IL17 (>/=0.1 ng/ml), however, induced severe cartilage degradation when given together with TNFalpha (>/=1 ng/ml). The cytokine combination decreased Alcian blue staining, a marker of proteoglycans, throughout the metatarsals and induced loss of the proliferating and early hypertrophic chondrocyte zones. TNFalpha alone also decreased Alcian blue staining, but not as dramatically as the cytokine combination. In addition, it did not induce loss of chondrocyte zones. Treatment with inhibitors of matrix metalloproteinase (MMP) activity and nitric oxide synthesis showed that MMP activity played a part in cartilage degradation, whereas nitric oxide production did not. CONCLUSIONS: IL17, together with TNFalpha, induced cartilage degradation in fetal mouse metatarsals in vitro. IL17 may, therefore, participate in the development of cartilage destruction associated with RA by enhancing the effects of TNFalpha and may provide a potential therapeutic target.

Animals↗
PubMed2002

Exposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesis.

Osteoblasts and adipocytes arise from a common progenitor cell in bone marrow. Whether estrogen directly regulates the progenitor cells differentiating into osteoblasts or adipocytes remains unknown. Using a mouse clonal cell line KS483 cultured in charcoal-stripped fetal bovine serum (FBS), we showed that 17beta-estradiol (E2) stimulates the differentiation of progenitor cells into osteoblasts and concurrently inhibits adipocyte formation in an estrogen receptor (ER)-dependent way. E2 increased alkaline phosphate (ALP) activity and nodule formation and stimulated messenger RNA (mRNA) expression of core-binding factor alpha-1 (Cbfa1), parathyroid hormone/parathyroid hormone-related protein receptors (PTH/PTHrP-Rs), and osteocalcin. In contrast, E2 decreased adipocyte numbers and down-regulated mRNA expression of peroxisome proliferator-activated receptor-gamma (PPARgamma)2, adipocyte protein 2 (aP2), and lipoprotein lipase (LPL). Furthermore, the reciprocal control of osteoblast and adipocyte differentiation by E2 was observed also in the presence of the adipogenic mixture of isobutylmethylxanthine, dexamethasone, and insulin. Immunohistochemical staining showed that ERalpha and ERbeta were present in osteoblasts and adipocytes. A new mouse splice variant ERbeta2 was identified, which differed in two amino acid residues from the rat isoform. E2 down-regulated mRNA expression of ERalpha, ERbeta1, and ERbeta2. The effects of E2 are not restricted to the KS483 cell line because similar results were obtained in mouse bone marrow cell cultures. Our results indicate that estrogen, in addition to stimulation of osteogenesis, inhibits adipogenesis, which might explain the clinical observations that estrogen-deficiency leads to an increase in adipocytes.

Adipocytes↗
PubMed2001

Effect of interleukin-17 on nitric oxide production and osteoclastic bone resorption: is there dependency on nuclear factor-kappaB and receptor activator of nuclear factor kappaB (RANK)/RANK ligand signaling?

Interleukin-17 (IL-17) is a proinflammatory cytokine produced exclusively by activated memory T cells and has recently been found to stimulate osteoclastic resorption. Like other proinflammatory cytokines, IL-17 may affect osteoclastic bone resorption indirectly via osteoblasts, possibly by mechanisms previously reported for chondrocytes that respond in very similarly to osteoblasts. As in chondrocytes, but only in combination with tumor necrosis factor-alpha (TNF-alpha), IL-17 induced nitric oxide (NO) production in osteoblastic cells and fetal mouse metatarsals by a nuclear factor-kappaB (NF-kappaB)-dependent mechanism. This effect was associated with elevated mRNA levels of the NF-kappaB isoforms RelA and p50. In fetal mouse metatarsals, IL-17 stimulated osteoclastic bone resorption only in combination with TNF-alpha. The pathway by which the cytokine combination exerts this effect was examined using inhibitors of NO synthesis and NF-kappaB activation. Although both inhibitors used abolished NO production, they did not prevent the stimulatory effect of the cytokine combination on osteoclastic resorption. In contrast, the inhibitors slightly increased osteoclastic resorption, suggesting a suppressive rather than stimulatory effect of NO on cytokine-induced bone resorption. In addition, we showed that IL-17 + TNF-alpha stimulated osteoclastic resorption independent of NF-kappaB signaling. To further examine the pathway by which osteoclastic resorption was stimulated, we used osteoprotegerin, a specific inhibitor of the receptor activator of NF-kappaB (RANK)/receptor activator of the NF-kappaB ligand (RANKL) pathway. Osteoprotegerin partially inhibited IL-17 + TNF-alpha-stimulated osteoclastic resorption only at the high concentration of 1000 ng/mL, whereas it completely blocked parathyroid hormone-related peptide-stimulated resorption at 300 ng/mL. In conclusion, IL-17 stimulated NO production by an NF-kappaB-dependent pathway in osteoblastic cells and fetal mouse metatarsals only in combination with TNF-alpha. Neither NO production nor NF-kappaB signaling, and only partly the RANK/RANKL pathway, were involved in the stimulatory effect of the cytokine combination on osteoblastic bone resorption in these long bones, suggesting the existence of other pathways by which osteoclastic resorption can be stimulated.

3T3 Cells↗
PubMed2001

Modulation of calcium oxalate monohydrate crystallization kinetics by urine of preterm neonates.

Preterm neonates frequently develop nephrocalcinosis (NC). However, the cause has not yet been elucidated. This study focuses on the effects of urine from preterm neonates on crystallization kinetics. Urine samples were collected and renal ultrasound examinations of preterm neonates (gestational age < 32 weeks) were performed during the first weeks of life, at term, and ages 6, 12, and 24 months. The effect of urine on crystallization was determined using a seeded crystal growth system, which measures the square root of solubility product ( radicalLc), percentage of growth inhibition (GI), and agglomeration inhibition ([tm]) of calcium oxalate crystals. Data for preterm neonates in the first weeks of life (n = 19) were compared with those for full-term neonates (n = 17) and healthy adults. Moreover, the correlation between [tm] and urinary (U)citrate level was studied. Mean radicalLc (0.27 +/- 0.1 versus 0.36 +/- 0.08 mmol/L) and mean [tm] (81 +/- 32 versus 143 +/- 97 minutes) were lower and mean Ucalcium-creatinine (2.20 +/- 1.74 versus 0.46 +/- 0.73 mol/mol) and Uoxalate-creatinine ratios (0.39 +/- 0.21 versus 0.16 +/- 0.09 mol/mol) were greater in preterm neonates in the first weeks of life compared with full-term neonates (p < 0.05). Furthermore, [tm] was less than the lower limit for healthy adults for all but one preterm neonate; [tm] increased and Ucalcium-creatinine and Uoxalate-creatinine ratios decreased with age (p < 0.005). There was a correlation between [tm] and citrate excretion (coefficient of 38; P < 0.001). Patients with and without NC at term did not differ statistically in mean radicalLc, percentage of GI, or [tm]. In conclusion, urine from preterm neonates in the first weeks of life is highly supersaturated and has a defective ability to inhibit calcium oxalate crystal agglomeration. This ability improves with age and is citrate mediated. We suggest that both the high level of supersaturation and defective ability to inhibit calcium oxalate crystal agglomeration contribute to the high incidence of NC.

Adult↗
PubMed2001

The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates.

In prostate cancer, the development of skeletal metastases is associated with a significant increase in morbidity, mainly because of severe bone pain, which eventually becomes refractory to conventional analgesia. Androgen ablation is the treatment of choice, but the majority of patients relapse within 2 to 3 years from initiation of treatment. After failure of hormone therapy, external-beam irradiation therapy is effective in the palliation of pain, but radionuclides represent an attractive and cost-effective alternative. Strontium 89 is currently the most commonly used radionuclide in the palliative management of prostate cancer metastatic to the skeleton. The rationale for the use of bisphosphonates in metastatic prostate cancer is not immediately obvious, given the predominantly osteoblastic nature of the metastatic process. The clinical use of these agents rests on a number of basic and clinical observations that provide ample evidence that, in prostate cancer, the metastatic process is associated with increased bone resorption. Evidence regarding the beneficial effects of bisphosphonates in reducing morbidity from metastatic prostate cancer is reasonably solid, although the choice of optimal bisphosphonate, mode of administration, dose, and duration of treatment must be determined in large, controlled studies before their widespread clinical use can be advocated. Available therapeutic modalities that use either radionuclides or bisphosphonates can effectively and safely be used in the palliative management of metastatic prostate cancer. Neither radionuclides nor bisphosphonates have been shown to prolong survival, but the potential of both agents to beneficially alter the metastatic process in prostate cancer is intriguing.

Bone Neoplasms↗
PubMed2001

Catabolic and anabolic signals in bone: therapeutic implications.

Bone remodelling accounts for the continuous renewal of the adult skeleton, and its disturbances constitute the pathophysiological basis of most skeletal disorders. Recently identified bone signalling pathways explain the action of known therapeutic agents and provide targets for new developments in the management of bone diseases.

Aging↗
PubMed2001

Clinical risk factors as predictors of postmenopausal osteoporosis in general practice.

BACKGROUND: Case-finding strategies to identify women with high risk for osteoporotic fractures have recently been proposed, but little information about such an approach in general practice is known. AIM: To study the validity of the proposed case-finding strategy for osteoporosis. DESIGN OF STUDY: Survey using case-finding strategy. SETTING: Seven hundred and twelve women aged between 55 and 84 years, randomly selected from a general practice in The Netherlands. METHOD: Of the 712 randomly selected women, 449 women participated. Information was obtained from a questionnaire, direct questioning, and computerised patients files. Bone mineral density of the femoral neck was measured by dual energy X-ray absorptiometry and vertebral morphometry was performed on lateral X-rays of the spine. Osteoporosis was defined by a bone mineral density T-score of less than 2.5 and/or the presence of severe vertebral deformities. Sensitivity, specificity, and predictive values were calculated for the whole set of risk factors; those significantly associated with osteoporosis and in logistic models. RESULTS: Clinical risk factors were present in 55% of the women and identified 68% of the women with osteoporosis. Three risk factors--a low body mass index, fragility fractures, and severe kyphosis and/or loss of height--were associated significantly with osteoporosis; they were present in 33% of the women and identified 60% of those with osteoporosis. A logistic model based on age and fragility fractures selected 32% of the women and identified 76%. CONCLUSION: No single risk factor could assist in identifying women with osteoporosis. A simplified case-finding strategy using only three risk factors, that is suitable for primary care, reduces the number of women to be evaluated by two-thirds; however, this is at the cost of missing the diagnosis in 40% of the women with osteoporosis. Addition of spine radiographs to the case-finding approach helped to obtain a better risk profile of the women and had also practical consequences for the management of some. We propose that radiographs should be included in any case-finding strategy.

Aged↗
PubMed2000

Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton.

BACKGROUND: Prostate carcinoma metastasizes frequently to the skeleton, causing significant morbidity, particularly severe bone pain. Metastatic lesions typically are osteosclerotic, but there is experimental, histologic, and biochemical evidence of increased bone resorption. Furthermore, bone resorption rates appear to correlate with bone pain. These observations provide the rationale for the use of bisphosphonates in the management of patients with prostate carcinoma and skeletal metastases. METHODS: The authors reviewed the literature and current findings on the use of biphosphonates in the management of patients with prostate carcinoma metastatic to the skeleton. RESULTS: Compared with the large number of studies with bisphosphonates in predominantly osteolytic bone disease, there have been relatively few (mostly uncontrolled) studies in patients with prostate carcinoma. Apart from the lack of appropriate experimental models, the osteoblastic nature of the metastases and the low incidence of objectively assessed endpoints of treatment (e.g., hypercalcemia, pathologic fractures) have delayed developments. Available data, however, strongly suggest that potent bisphosphonates are efficacious in reducing skeletal morbidity in patients with prostate carcinoma. CONCLUSIONS: For the optimal management of patients with skeletal metastases from prostate carcinoma with bisphosphonates their mode of administration, the dose and duration of treatment need to be evaluated. Better understanding of the cellular and molecular mechanisms underlying bone metastases can lead to the design of improved treatment protocols with potent bisphosphonates.

Bone Neoplasms↗
PubMed2000

The relationship between phalangeal bone density and vertebral deformities.

Radiographic absorptiometry (RA) of the phalanges is a convenient and reliable technique for measuring bone mineral density (BMD). It needs only a radiograph of the hand, which can be sent for evaluation to a central facility, whereas other techniques require specialized equipment. We assessed the relationship between RA measurements and the presence of vertebral deformities in a population-based cohort of postmenopausal women, and to compare the results with simultaneously obtained BMD of the hip by dual-energy X-ray absorptiometry (DXA). A total of 389 women aged 55-84 (mean age 67.2 years, SD 8.7) were randomly selected from a large general practice. RA, DXA of the hip, and vertebral deformities in the lateral spine X-rays by vertebral morphometry were assessed. Thirty-eight women (9.8%) had severe (grade II) vertebral deformities, and their BMD at the phalanges and femoral neck was significantly lower than that of women without severe vertebral deformities. Odds ratios for the presence of severe vertebral deformities of 1.5 (95% CI: 1.1-2.1) for RA and 1.3 (95% CI: 0.9-1. 9) for DXA, together with similar receiver operating characteristics curves, were found using age-adjusted logistic regression. Phalangeal BMD is related to vertebral deformities at least as closely as BMD of the femoral neck BMD. RA may therefore help to evaluate fracture risk, especially if no DXA equipment is available.

Absorptiometry, Photon↗
PubMed2000

Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation.

Endochondral bone formation is regulated by systemically and locally acting growth factors. A role for vascular endothelial growth factor (VEGF) in this process has recently been proposed, because inactivation of VEGF inhibits endochondral bone formation via inhibition of angiogenesis. Despite the known effect of VEGF as specific endothelial growth factor, its effects on osteoblast differentiation have not been studied. We, therefore, examined the expression of VEGF-A, -B, -C, and -D and their receptors in a model of osteoblast differentiation using the mouse preosteoblast-like cell line KS483. Early in differentiation, KS483 cells express low levels VEGF-A, -B, and -D messenger RNA, whereas during mineralization, KS483 cells express high levels. In addition, expression of the VEGF receptors, VEGFR1, VEGFR2, and VEGF165R/neuropilin, coincided with expression of their ligands, being maximally expressed during mineralization. VEGF-A production during osteoblast differentiation was stimulated by insulin-like growth factor I that enhances osteoblast differentiation and was inhibited by PTH-related peptide that inhibits osteoblast differentiation. Furthermore, continuous treatment of KS483 cells with recombinant human VEGF-A stimulated nodule formation. Although treatment of KS483 cells with soluble FLT1, an agent that blocks binding of VEGF-A and -B to VEGFR1, did not inhibit nodule formation, this observation does not exclude involvement of VEGFR2 in the regulation of osteoblast differentiation. As it is known that VEGF-A, -C, and -D can act through activation of VEGFR2, other isoforms might compensate for VEGF-A loss. The expression pattern of VEGFs and their receptors shown here suggests that VEGFs play an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation.

Animals↗