Changes in serum receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34)

Changes in biochemical markers of bone turnover following intermittent injections of human (h)PTH (1-34) suggest that bone formation is initially favored over bone resorption. hPTH (1-34) is also known to influence osteoclast maturation and activity through modulation of osteoblast-derived cytokines, such as receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), IL-6, and IL-6 soluble receptor (IL-6sR). In this experiment, we investigated the changes in serum levels of soluble RANKL (sRANKL), OPG, IL-6, and IL-6sR in patients with glucocorticoid-induced osteoporosis treated with hPTH (1-34). Fifty-one postmenopausal women with glucocorticoid-induced osteoporosis were randomized to receive 12 months of 400 U hPTH (1-34) ( approximately 40 microg) daily and standard hormone replacement therapy, or hormone replacement therapy alone. Serum levels of sRANKL, OPG, IL-6, and IL-6sR were measured at baseline, 1 month, and every 3 months thereafter for a total of 24 months. hPTH (1-34) caused a rapid and significant increase in sRANKL within 1 month, and the levels remained elevated throughout the duration of therapy. IL-6 and IL-6sR increased significantly within 1 month, but returned to baseline levels more rapidly. In contrast, OPG was mildly suppressed beginning 6 months after hPTH therapy. These data support the hypothesis that hPTH (1-34) initially stimulates osteoblast maturation and function, which in turn leads to osteoclast activation and a gradual rebalancing of bone formation and resorption.     

The effect of teriparatide on serum Dickkopf‐1 levels in postmenopausal women with established osteoporosis

Objective Parathyroid hormone increases the differentiation of osteoblast precursors through canonical wingless (Wnt) signalling, resulting in an osteoanabolic effect. We aimed to evaluate serum levels of the Wnt‐inhibitor Dickkopf‐1 (Dkk‐1) in postmenopausal women with established osteoporosis and their changes with teriparatide (TPTD – human recombinant PTH 1–34). Design and patients A total of 31 postmenopausal Caucasian women with established osteoporosis (mean age 66·3 ± 1·4 years) received daily injections of 20 μg TPTD for 18 months. Follow‐up was continued for another 6 months after treatment discontinuation (total duration of treatment 24 months). Measurements Serum samples for total calcium (Ca), intact PTH (iPTH), bone‐specific alkaline phosphatase, C‐terminal cross‐linking telopeptide of type 1 collagen (CTx) and Dkk‐1 were obtained at baseline, and at 6, 18 and 24 months after TPTD initiation. Lumbar spine bone mineral density (BMD) was measured before and after 18 months of TPTD treatment. A total of 16 age‐ and gender‐matched healthy controls were also analysed at baseline. Results Serum Dkk‐1 levels at baseline were significantly higher in osteoporotic women compared with that in controls (P < 0·002). Dkk‐1 increased significantly during TPTD administration (P < 0·044) and decreased to baseline 6 months after TPTD discontinuation. Dkk‐1 change was positively correlated to Ca (r = 0·530, P = 0·004) and negatively correlated to iPTH change (r = ?0·398, P = 0·040). There was no correlation between Dkk‐1 and BMD changes. Conclusions Our data suggest that Dkk‐1 levels are increased in women with postmenopausal osteoporosis. TPTD therapy results in further increase of Dkk‐1 that may be compensative to TPTD‐induced enhanced Wnt signalling.     

Circulating levels of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably healthy human population

OBJECTIVES: To determine the ranges of variation of circulating receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG)/macrophage-colony stimulating factor(M-CSF) and to ascertain their potential relationships with age, sex and menopausal status in women, and with sex hormones in a population-based healthy cohort. SUBJECTS AND METHODS: Blood samples were collected with EDTA after an overnight fast. The plasma levels of each of the above biochemical indices were measured by ELISA in a total of 566 apparently healthy individuals aged 18-75 years. RESULTS: The plasma concentrations of cytokine molecules in the entire sample ranged from 674 to 4929 pg/ml for OPG, from 105 to 4468 pg/ml for soluble RANKL (sRANKL), and from 187 to 7604 pg/ml for M-CSF. The OPG levels demonstrated a clear positive correlation with age in both sexes (r=0.42 and 0.43, P<0.001, for men and women respectively). Application of the two-interval mathematical model revealed that in females OPG levels were age-independent until age 42, but then showed clear and significant correlation with age (r=0.48, P<0.001). As a result, young females (before 42 years) had a substantially lower average OPG level, 1377.8+/-327.68 pg/ml, in comparison with older women, 1666.02+/-397.14 pg/ml. The M-CSF correlation with age was significantly greater in women (r=0.29, P<0.001) compared with men (r=0.17, P<0.01). Significant negative correlations between plasma levels of both OPG and M-CSF with estradiol concentrations were observed in women (r=-0.39, P<0.01; r=-0.25, P<0.001 respectively). sRANKL did not correlate with either age or sex hormones in either women or men. CONCLUSION: Age and sex affect differently the interindividual variation of OPG, RANKL and M-CSF. Our observations could form the basis for further research to establish provisional reference limits for OPG and RANKL, which are potential markers for benign and malignant processes in bone.     

The role of the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism

CONTEXT: The mechanisms of action of PTH on bone in vivo remain incompletely understood. The objective of this investigation was to examine changes in serum levels of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin (OPG) in primary hyperparathyroidism and their relationship to bone loss. PATIENTS AND METHODS: Twenty-nine patients with primary hyperparathyroidism had baseline circulating soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) and OPG measured. The relationship to biochemical markers of bone turnover and changes in bone mineral density over 2 yr was examined. RESULTS: Baseline sRANKL levels were elevated (1.7+/-0.1 pmol/liter), whereas OPG remained in the normal range (5.6+/-0.4 pmol/liter). Circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption (urine deoxypyridinoline cross-links: r=0.51, P<0.01; serum N-telopeptide of type I collagen: r=0.37, P<0.05). Furthermore, sRANKL correlated with both IL-6 and IL-6 soluble receptor (IL-6sR) (r=0.47, P<0.05 and r=0.55, P<0.005, respectively). Serum sRANKL levels also correlated with bone loss at the total femur (r=-0.53, P<0.01). Lastly, a high value of sRANKL in combination with values of IL-6 and IL-6sR in the upper quartile (sRANKL>or=1.81 pg/ml, IL -6>or=11.8 pg/ml, and IL-6sR>or=45.6 ng/ml) defined a group of four women with significantly greater rates of bone loss at the total femur than the remaining patients (-2.7+/-1.7% vs. +0.5+/-0.3%; n=4 vs. n=19, P<0.05). CONCLUSION: Determination of circulating levels of sRANKL may be useful in identifying patients with mild primary hyperparathyroidism at greater risk for bone loss. The fact that circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption suggests that skeletal responsiveness to PTH may differ in this disease.     

IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo

IGF-I, a ubiquitous polypeptide, plays a key role in longitudinal bone growth and acquisition. The most predominant effect of skeletal IGF-I is acceleration of the differentiation program for osteoblasts. However, in vivo studies using recombinant human (rh) IGF-I and/or rhGH have demonstrated stimulation of both bone formation and resorption, thereby potentially limiting the usefulness of these peptides in the treatment of osteoporosis. In this study, we hypothesized that IGF-I modulates bone resorption by regulating expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) in bone cells. Using Northern analysis in ST2 cells, we found that human IGF-I suppressed OPG mRNA in a time- and dose-dependent manner: 100 micro g/LIGF-I (13 nM) decreased OPG expression by 37.0 +/- 1.8% (P < 0.002). The half maximal inhibitory dose of IGF-I was reached at 50 micro g/liter ( approximately 6.5 nM) with no effect of IGF-I on OPG message stability. Conditioned media from ST2 cells confirmed that IGF-I decreased secreted OPG, reducing levels by 42%, from 12.1-7 ng/ml at 48 h (P < 0.05). Similarly, IGF-I at 100 micro g/liter (13 nM) increased RANKL mRNA expression to 353 +/- 74% above untreated cells as assessed by real-time PCR. In vivo, low doses of rhGH when administered to elderly postmenopausal women only modestly raised serum IGF-I (to concentrations of 18-26 nM) and did not affect circulating OPG concentrations; however, administration of rhIGF-I (30 micro g/kg.d) for 1 yr to older women resulted in a significant increase in serum IGF-I (to concentrations of 39-45 nM) and a 20% reduction in serum OPG (P < 0.05). In summary, we conclude that IGF-I in a dose- and time-dependent manner regulates OPG and RANKL in vitro and in vivo. These data suggest IGF-I may act as a coupling factor in bone remodeling by activating both bone formation and bone resorption; the latter effect appears to be mediated through the OPG/RANKL system in bone.     

Intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in osteoblasts

Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) produced by osteoblasts/stromal cells are involved as positive and negative regulators in osteoclast formation. Three independent signals have been proposed to induce RANKL expression in osteoblasts/stromal cells: vitamin D receptor-, cAMP-, and gp130-mediated signals. We previously reported that intracellular calcium-elevating compounds such as ionomycin, cyclopiazonic acid, and thapsigargin induced osteoclast formation in cocultures of mouse bone marrow cells and primary osteoblasts. Increases in calcium concentration in culture medium also induced osteoclast formation in cocultures. Treatment of primary osteoblasts with these compounds or with high calcium medium stimulated the expression of both RANKL and OPG messenger RNAs (mRNAs). 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)-tetra(acetoxymethyl)ester, an intracellular calcium chelator, suppressed both ionomycin-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, also stimulated osteoclast formation in these cocultures and the expression of RANKL and OPG mRNAs in primary osteoblasts. Protein kinase C inhibitors such as calphostin and staurosporin suppressed ionomycin- and PMA-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Ionomycin stimulated RANKL mRNA expression in ST2 and MC3T3-G2/PA6 cells, but not in MC3T3-E1 or NIH-3T3 cells. These effects were closely correlated with osteoclast formation in response to ionomycin in cocultures with these stromal cell lines. OPG strongly inhibited osteoclast formation induced by calcium-elevating compounds and PMA in cocultures, suggesting that RANKL expression in osteoblasts is a rate-limiting step for osteoclast induction. Forskolin, an activator of cAMP signals, also stimulated osteoclast formation in cocultures. Forskolin enhanced RANKL mRNA expression but suppressed OPG mRNA expression in primary osteoblasts. These results suggest that the calcium/protein kinase C signal in osteoblasts/stromal cells is the fourth signal for inducing RANKL mRNA expression, which, in turn, stimulates osteoclast formation.     

Acute and chronic effect of teriparatide on glucose metabolism in women with established osteoporosis.

There is indirect evidence of unfavorable effects of parathyroid hormone (PTH) on glucose metabolism. Teriparatide (recombinant human PTH 1-34-TPTD) has recently been available for the treatment of osteoporosis. The aim of this prospective study was to evaluate the acute and chronic effect of TPTD on blood glucose and insulin levels in women with established osteoporosis. Twenty-three postmenopausal women with established osteoporosis (mean age 65.6+/-1.8 years) received daily injections of 20 mg TPTD for six months. Three oral glucose tolerance tests (OGTT) were performed: one day before the first injection (OGTT-basal), one hour after (OGTT-acute) and six months after initiation of therapy (OGTT-chronic). There were significant differences between the OGTT-basal and OGTT-acute values in glucose at 90 min (168.3+/-9.8 vs. 180.6+/-9.2, p<0.05) and 120 min (152.0+/-8.7 vs. 170.5+/-7.8, p<0.01), between the OGTT-basal and OGTT-chronic values for glucose at 90 min (168.3+/-9.8 vs. 184.5+/-13.3, p<0.05) and between the OGTT-basal and OGTT-acute for insulin at 90 min (56.7+/-7.4 vs. 68.7+/-8.2, p<0.01). These differences remained significant for the subgroup of patients with normal (n=8) but not impaired glucose tolerance or diabetes mellitus (n=15). TPTD seems to have an acute, subclinical adverse impact on stimulated glucose levels, possibly due to insulin resistance. This impact tends to subside when TPTD is continued on a chronic basis.     

Glucocorticoid regulation of osteoclast differentiation and expression of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand, osteoprotegerin, and receptor activator of NF-kappaB in mouse calvarial bones

In the present study, dexamethasone treatment of neonatal mouse calvarial bones increased mRNA expression of tartrate-resistant acid phosphatase, calcitonin receptor (CTR), cathepsin K, carbonic anhydrase II, osteoprotegerin (OPG), and receptor activator of nuclear factor-kappaB (RANK) as well as mRNA and protein expression of RANK ligand (RANKL). The increase in OPG mRNA noted with dexamethasone was in contrast to 1,25(OH)(2)-vitamin D3 (D3) treatment, which decreased OPG expression. Stimulation of (45)Ca release by dexamethasone and hydrocortisone in calvariae was blocked by OPG. Stimulation of RANKL, RANK, OPG, and CTR mRNA expression by dexamethasone in calvariae was blocked by the glucocorticoid receptor antagonist RU 38,486. Greater than additive potentiations of CTR mRNA and RANKL mRNA and protein were observed when D3 and dexamethasone were combined. Vitamin D receptor mRNA was increased by dexamethasone and D3, whereas glucocorticoid receptor (GR) mRNA was decreased by dexamethasone and unaffected by D3. No synergistic interaction between dexamethasone and D3 on either vitamin D receptor or GR mRNA expression was noted. The data demonstrate that dexamethasone-induced bone resorption in calvarial bones is associated with increased differentiation of osteoclasts and regulation of the RANKL-RANK-OPG system. The increase in OPG expression and the decrease of GR expression noted with dexamethasone offer an explanation for why bone breakdown in mouse calvariae treated with glucocorticoids is less than that caused by resorptive agents like D3. The synergistic stimulation of RANKL by dexamethasone and D3 offers an explanation of how glucocorticoids and D3 interact to potentiate bone resorption.     

CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications

CONTEXT: Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism. EVIDENCE ACQUISITION: A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system. EVIDENCE SYNTHESIS: RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma. CONCLUSIONS: The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.     

Osteoblasts provide a suitable microenvironment for the action of receptor activator of nuclear factor-kappaB ligand

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption. Serum concentrations of RANKL are extremely high in OPG-deficient (OPG(-/-)) mice, suggesting that circulating RANKL is involved in osteoclastogenesis. RANKL(-/-) mice exhibit osteopetrosis, with the absence of osteoclasts. We examined the requirements for osteoclastogenesis using OPG(-/-) mice, RANKL(-/-) mice, and a system involving bone morphogenetic protein 2 (BMP-2)-induced ectopic bone formation. When collagen disks containing BMP-2 (BMP-2-disks) or vehicle were implanted into OPG(-/-) mice, osteoclast-like cells (OCLs) and alkaline phosphatase-positive OCLs appeared in BMP-2-disks but not the control disks. F4/80-positive osteoclast precursors were similarly distributed in both BMP-2- and control disks. Cells expressing RANKL were detected in the BMP-2-disks, and the addition of OPG to the disk inhibited OCL formation. Muscle cells in culture differentiated into alkaline phosphatase-positive cells in the presence of BMP-2 and accordingly expressed RANKL mRNA in response to PTH. This suggests that RANKL expressed by osteoblasts is a requirement for osteoclastogenesis. We then examined how osteoblasts are involved in osteoclastogenesis other than RANKL expression, using RANKL(-/-) mice. BMP-2- and control disks were implanted into RANKL(-/-) mice, which were injected with RANKL for 7 d. Many OCLs were observed in the BMP-2-disks and bone tissues but not the control disks. These results suggest that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.     

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand mRNA expression in patients with rheumatoid arthritis and healthy controls

OBJECTIVE: To further understand the role of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANK-L) in rheumatoid arthritis (RA), we studied the levels of RANK-L and OPG mRNA in peripheral blood mononuclear cells (PBMC) and synovial tissue of patients with RA and controls. METHODS: RANK-L and OPG mRNA levels were measured in PBMC and CD4+/CD8+ T cell subsets of patients with chronic RA, osteoarthritis (OA), and healthy controls, using quantitative real-time polymerase chain reaction. OPG and RANK-L mRNA levels were measured in paired blood and synovial tissue samples of patients with early, untreated RA at 2 timepoints with an interval of 16 weeks. RESULTS: RANK-L mRNA levels were significantly higher in PBMC of patients with early and chronic RA compared to healthy controls. Contrary to healthy controls, RANK-L mRNA levels in patients with chronic RA were mainly of CD4+ T cell origin. OPG mRNA was observed in the blood of all (17/17) early RA patients, but could not be detected in chronic RA patients (0/14) or in patients with OA (0/8). Three out of 17 healthy controls showed measurable levels of OPG mRNA. The OPG/RANK-L ratio tended to be higher in the synovium than in the PBMC of early RA patients. RANK-L mRNA in synovial tissue was mainly of non-T cell origin. CONCLUSION: Since RANK-L and OPG mRNA levels are elevated in PBMC of RA patients, and CD4+ T cells are the major contributors to RANK-L mRNA expression, mononuclear cells in patients with RA may be involved in the pathways that regulate bone metabolism.     

Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment

CONTEXT: The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor. EVIDENCE: This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease. EVIDENCE SYNTHESIS: Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements. CONCLUSIONS: The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.     

20～75岁妇女血清护骨素、核因子-κB受体活化子配体的变化与年龄、停经、骨生化指标和骨密度的关系

目的　研究血清护骨素 (OPG)和核因子 κB受体活化子配体 (RANKL)与年龄、停经、骨生化指标和骨密度的关系 ,了解影响血清OPG和RANKL的因素。方法　在 5 0 4例 2 0～ 75岁的绝经前和绝经后妇女中 ,以双能X线吸收仪测定腰椎和股骨各处骨密度。按WHO标准 ,将绝经后妇女分为骨量正常、骨量减少和骨质疏松 3组。测定血清骨钙素 (BGP)、尿Ⅰ型胶原交联N端肽 (NTx)、血清OPG和RANKL ,计算RANKL/OPG比值。结果　年龄与血清OPG正相关 (r =0 4 4 2 ,P <0 0 0 1) ,与血清RANKL负相关 (r=- 0 2 6 3,P <0 0 0 1)。绝经后妇女的血清OPG(10 7 6± 3 0 )ng/L明显高于绝经前妇女 (72 0± 1 8)ng/L ,而血清RANKL(4 7± 0 4 )ng/L显著低于绝经前妇女 (5 8± 0 3)ng/L。校正年龄、停经年限和体重指数后 ,血清OPG、RANKL与腰椎和股骨各处骨密度无相关性。血清OPG与尿NTx/肌酐正相关 ;血清RANKL与血清BGP负相关。血清OPG和RANKL在绝经后骨质疏松组、骨量减少组和正常骨量组间差异无显著性。多元逐步回归分析显示 ,年龄、停经年限和骨转换指标是决定血清OPG RANKL系统的独立因素。结论　随年龄而升高的血清OPG可能是人体对抗绝经后骨吸收加快的一个代偿性反应 ,随年龄而下降的血清RANKL可能有益于恢复绝经后妇女的骨     

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.     

Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.