Biomedical subjects

Ulf H Lerner

Publications and source records attributed to Ulf H Lerner.

15 recordsLinked to original sources

PubMed2006

Osteoclast formation is strongly reduced both in vivo and in vitro in the absence of CD47/SIRPalpha-interaction.

Physical interaction between the cell surface receptors CD47 and signal regulatory protein alpha (SIRPalpha) was reported to regulate cell migration, phagocytosis, cytokine production, and macrophage fusion. However, it is unclear if the CD47/SIRPalpha-interaction can also regulate macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-stimulated formation of osteoclasts. Here, we show that functional blocking antibodies to either CD47 or SIRPalpha strongly reduced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)+ osteoclasts in cultures of murine hematopoietic cells, stimulated in vitro by M-CSF and RANKL. In addition, the numbers of osteoclasts formed in M-CSF/RANKL-stimulated bone marrow macrophage cultures from CD47-/- mice were strongly reduced, and bones of CD47-/- mice exhibited significantly reduced osteoclast numbers, as compared with wild-type controls. We conclude that the CD47/SIRPalpha interaction is important for M-CSF/RANKL-stimulated osteoclast formation both in vivo and in vitro, and that absence of CD47 results in decreased numbers of osteoclasts in CD47-/- mice.

Animals↗

PubMed2006

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.

Animals↗

PubMed2005

Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway.

Interleukin (IL)-4 and IL-13 are cytokines that inhibit bone resorption. Data showing an inhibitory effect of IL-4 and IL-13 on RANK mRNA in mouse calvariae were first reported at the 22nd American Society for Bone and Mineral Research Meeting (Lerner, U.H., and Conaway, H. H. 2000) J. Bone Min. Res. 15, Suppl. 1, Abstr. SU 230). In the present study, release of 45Ca from cultured mouse calvarial bones stimulated by different cytokines, peptides, and steroid hormones was inhibited by IL-4 and IL-13. IL-4 and IL-13 decreased receptor activator of nuclear factor-kappaB ligand (RANKL) and RANK mRNA and increased osteoprotegerin (OPG) mRNA in calvariae. Additionally, the cytokines decreased RANKL protein and increased OPG protein in calvarial bones. In osteoblasts isolated from calvariae, both an increase in RANKL mRNA and a decrease in OPG mRNA and protein elicited by vitamin D3 were reversed by IL-4 and IL-13. IL-4 and IL-13 decreased the number of tartrate-resistant acid phosphatase positive multinucleated cells and the mRNA expression of calcitonin receptor, tartrate-resistant acid phosphatase, and cathepsin K in mouse spleen cells and bone marrow macrophages (BMM) treated with macrophage colony-stimulating factor and RANKL. Inhibition of mRNA for RANK and the transcription factor NFAT2 was also noted in spleen cell and BMM cultures treated with IL-4 and IL-13. In addition, RANK mRNA and RANK protein were decreased by IL-4 and IL-13 in RAW 264.7 cells. Osteoblasts, spleen cells, and BMM expressed mRNA for the four proteins making up the IL-4 and IL-13 receptors. No effects by IL-4 on bone resorption and osteoclast formation or on RANKL and RANK mRNA expression were seen in Stat6-/- mice. The data indicate that IL-4 and IL-13, via a STAT6-dependent pathway, inhibit osteoclast differentiation and bone resorption by activating receptors on osteoblasts and osteoclasts that affect the RANKL/RANK/OPG system.

Animals↗

PubMed2005

The neuropeptide VIP potentiates IL-6 production induced by proinflammatory osteotropic cytokines in calvarial osteoblasts and the osteoblastic cell line MC3T3-E1.

Skeletal turnover is orchestrated by a complex network of regulatory factors. Lately, regulation of bone metabolism through neuro-osteological interactions has been proposed. Here, we address the question whether IL-6 production can be affected by interactions between the neuropeptide VIP and proinflammatory, bone-resorbing cytokines. By using calvarial osteoblasts, we showed that IL-1beta increased IL-6 production time- and concentration-dependently, and that these effects were potentiated by VIP. Furthermore, IL-1beta stimulated IL-6 promoter activity in the osteoblastic cell line MC3T3-E1 stably transfected with a human IL-6 promoter/luciferase construct, and both VIP, and the related neuropeptide PACAP-38, increased the effect of IL-1beta in a synergistic manner. The IL-6 protein release from calvarial osteoblasts was also stimulated by the osteoclastogenic, proinflammatory cytokines IL-11, LIF, OSM, IL-17, TGF-beta, and TNF-alpha. All effects, except for that of TNF-alpha, were synergistically potentiated by VIP. These findings further support the role of neuropeptides, and the presence of neuro-immunological interactions, in bone metabolism.

3T3 Cells↗

PubMed2005

Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts.

Interleukin-6 (IL-6), and the related cytokines IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), are potent stimulators of osteoclastic bone resorption. In the present study, we have addressed the possibility that the neuropeptide vasoactive intestinal peptide (VIP) may regulate the production of and/or sensitivity to the IL-6 family of cytokines in mouse calvarial osteoblasts. VIP stimulated IL-6 mRNA expression and protein release in a time- and concentration-dependent manner, whereas mRNA expression of the IL-6 receptor, as well as mRNA expressions of IL-11, LIF, OSM and their cognate receptors, were unaffected by VIP. In cells transfected with the IL-6 promoter coupled to luciferase, VIP increased transcriptional activity. The effects of VIP were shared by the related neuropeptide PACAP-38, belonging to the same superfamily of neuropeptides, whereas secretin did not have any effect, indicating that the effects were mediated by VPAC2 receptors. The effects of VIP were potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram and mimicked by forskolin, indicating the involvement of the cyclic AMP/protein kinase A pathway. This was further demonstrated by the facts that the stimulatory effect of VIP on luciferase activity could be reversed by the PKA inhibitors H-89 and KT5720 and was mimicked by cyclic AMP analogues selective for PKA, but not by those selective for Epac. In addition, VIP enhanced the phosphorylation of CREB, as assessed by both immunocytochemical analysis and Western blot. The DNA binding activity of nuclear extracts to C/EBP was increased by VIP, whereas binding to AP-1 was decreased. In contrast, DNA binding to NF-kappaB, as well as nuclear translocation of NF-kappaB and C/EBP, were unaffected by VIP. The mRNA expressions of C/EBPbeta, C/EBPdelta, C/EBPgamma, c-Jun, JunB, c-Fos, Fra-1 and IkappaBalpha and protein level of IkappaBalpha were all unaffected by VIP. These observations, together, demonstrate that VIP stimulates IL-6 production in osteoblasts by a mechanism likely to be mediated by VPAC2 receptors and dependent on cyclic AMP/protein kinase A/CREB activation and also involving the transcription factors C/EBP and AP-1.

3T3 Cells↗

PubMed2004

Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.

Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.

Aged↗

PubMed2004

Osteoclastogenesis is decreased by cysteine proteinase inhibitors.

The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.

Animals↗

PubMed2004

Bone resorbing activity and cytokine levels in gingival crevicular fluid before and after treatment of periodontal disease.

BACKGROUND: The aim of the present study was to investigate bone resorption activity (BRA), interleukin-1 alpha (IL-1 alpha), IL-1 beta and interleukin-1 receptor antagonist (IL-1ra) in gingival crevicular fluid (GCF) in sites with no signs of periodontal disease and in sites with horizontal or angular loss of periodontal bone. These assessments were performed before and after periodontal treatment. METHODS: GCFs were collected from 10 individuals with filter strips from two healthy sites and four sites with deep pathological periodontal pockets, two of which showed horizontal bone loss and two with angular bone loss. All diseased pockets were treated with flap surgery and systemic Doxyferm. Twelve months later GCF was collected again and treatment outcome evaluated. BRA in GCFs was assessed in a bone organ culture system by following the release of (45)Ca from neonatal mouse calvariae. The amounts of IL-1 alpha, IL-1 beta and IL-1ra in GCFs were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment resulted in reduction of pocket depths with 3.5+/-0.5 mm in sites with angular bone loss and 2.8+/-0.3 mm in sites with horizontal bone loss. Initially, BRA, IL-1 alpha, IL-1 beta and IL-1ra were significantly higher in GCFs from diseased sites compared with healthy sites. No differences in BRA and cytokine levels were seen between GCFs from pockets with horizontal and angular bone losses. The levels of IL-1 alpha, IL-1 beta and IL-1ra were significantly reduced after treatment of diseased pockets. Pocket depths were significantly correlated to BRA only in pre-treatment sites with angular bone loss. BRA was correlated to Il-1 alpha, IL-1 beta, but not to IL-1ra, in diseased sites with angular bone loss, before and after treatment. The reductions of BRA in the individual sites, seen after treatment, were not correlated to the reductions of Il-1 alpha, IL-1 beta or IL-1ra. CONCLUSIONS: These data show that BRA and cytokine levels are increased in GCFs from sites with periodontal disease and that periodontal treatment results in reduction of the cytokines. Our findings further indicate that IL-1 alpha and IL-1 beta play important roles for the BRA present in GCFs, but that other factors also contribute to this activity.

Aged↗

PubMed2003

cDNA-arrays and real-time quantitative PCR techniques in the investigation of chronic Achilles tendinosis.

The aetiology and pathogenesis of chronic painful Achilles tendinosis are unknown. This investigation aimed to use cDNA arrays and real-time quantitative polymerase chain reaction (real-time PCR) technique to study tendinosis and control tissue samples. Five patients (females mean age 57.1+/-4.3 (years+/-SD)) with chronic painful Achilles tendinosis were included. From all patients, one biopsy was taken from the area with tendinosis and one from a clinically normal area (control) of the tendon. The tissue samples were immediately immersed in RNAlater and frozen at -80 degrees C until RNA extraction. Portions of pooled RNA from control and tendinosis sites, respectively, were transcribed to cDNA, radioactively labelled (32P), hybridized to cDNA expression arrays, and exposed to phosphoimager screens over night. Expressions of specific genes, shown to be regulated in the cDNA array analysis, were analyzed in the individual samples using real-time PCR. cDNA arrays showed that gene expressions for matrix-metalloproteinase-2 (MMP-2), fibronectin subunit B (FNRB), vascular endothelial growth factor (VEGF), and mitogen-activated protein kinase p38 (MAPKp38) were up-regulated, while matrix-metalloproteinase-3 (MMP-3) and decorin were down-regulated, in tendinosis tissue compared with control tissue. Using real-time PCR, 4/5 and 3/5 patients showed up-regulation of MMP-2 and FNRB mRNA, respectively. For decorin, VEGF, and MAPKp38, real-time PCR revealed a great variability among patients. Interestingly, the mRNAs for several cytokines and cytokine receptors were not regulated, indicating the absence of an inflammatory process in chronic painful Achilles tendinosis. In conclusion, cDNA-arrays and real-time PCR can be used to study differences in gene expression levels between tendinosis and control tendon tissue.

Achilles Tendon↗

PubMed2002

IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae.

IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) are IL-6-type cytokines that stimulate osteoclast formation and function. In the present study, the resorptive effects of these agents and their regulation of receptor activator of NF-kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG) were studied in neonatal mouse calvaria. When tested separately, neither human (h) IL-6 nor the human soluble IL-6R (shIL-6R) stimulated bone resorption, but when hIL-6 and the shIL-6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted. Semiquantitative RT-PCR showed that hIL-6 plus shIL-6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression. Human LIF, hOSM, and mouse OSM (mOSM) also stimulated 45Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calvaria, but had no effect on the expression of RANK. In agreement with the RT-PCR analyses, ELISA measurements showed that both hIL-6 plus shIL-6R and mOSM increased RANKL and OPG proteins. 1,25-Dihydroxyvitamin D3 (D3) also increased the RANKL protein level, but decreased the protein level of OPG. OPG inhibited 45Ca release stimulated by RANKL, hIL-6 plus shIL-6R, hLIF, hOSM, mOSM, and D3. An Ab neutralizing mouse gp130 inhibited 45Ca release induced by hIL-6 plus shIL-6R. These experiments demonstrated stimulation of calvarial bone resorption and regulation of mRNA and protein expression of RANKL and OPG by D3 and IL-6 family cytokines as well as regulation of RANK expression in preosteoclasts/osteoclasts of mouse calvaria by D3 and hIL-6 plus shIL-6R.

Animals↗

PubMed2002

Expression and regulatory role of receptors for vasoactive intestinal peptide in bone cells.

An intense network of nerve fibers can be demonstrated in skeletal tissues, not only in the periosteum but also within cortical bone, growth plate, and bone marrow. This neuro-osteogenic network expresses a restricted number of signalling molecules, including neuropeptides, neurotransmitters, and neurotrophins. Several lines of evidence indicate that receptors for these molecules are present on bone cells and that activation of these receptors leads to changes in bone cell activities. In addition, deletion of signalling molecules has been shown to alter bone metabolism. In the present review, these studies are summarized with a focus on distribution and effects of vasoactive intestinal peptide.

Animals↗

PubMed2002

Characterization of bradykinin receptors in a human osteoblastic cell line.

Bradykinin receptor subtypes linked to prostaglandin release have been assessed in a human osteosarcoma cell line with osteoblastic phenotype (MG-63). Bradykinin (BK; 1 micromol/l) caused a burst of prostaglandin E(2) release that was maximal at 10 min. When the effect on the burst of PGE(2) and PGI(2) release by a variety of kinins and kinin analogues was assessed, the following rank order of response was found: Lys-BK>BK> or =Met-Lys-BK>Ile-Ser-BK>[Tyr(8)]-BK> or =[Hyp(3)]-BK>>>des-Arg(9)-BK=des-Arg(10)-Lys-BK=des-Arg(1)-BK, [Thi(5,8),D-Phe(7)]-BK=Sar-[D-Phe(8)]-des-Arg(9)-BK=Tyr-Gly-Lys-Aca-Lys-des-Arg(9)-BK. The rapid effect of BK on PGE(2) and PGI(2) release was unaffected by des-Arg(9)-[Leu(8)]-BK, des-Arg(10)-[Leu(9)]-Lys-BK and des-Arg(10)-[Hoe 140], but strongly inhibited by Hoe 140 in a concentration-dependent manner. When the incubation time was extended to 48 h, it was found that des-Arg(9)-BK and des-Arg(10)-Lys-BK caused a delayed enhancement of the formation of PGE(2). When PGE(2) formation was assessed in 24-h experiments, the following rank order of response was obtained: Tyr-Gly-Lys-Aca-Lys-des-Arg(9)-BK>>BK=Lys-BK>>des-Arg(10)-Lys-BK>Sar[D-Phe(8)]-des-Arg(9)-BK>des-Arg(9)-BK. The stimulatory effect of BK at 24 h was unaffected by des-Arg(9)-[Leu(8)]-BK, des-Arg(10)-[Leu(9)]-Lys-BK and des-Arg(10)-[Hoe 140] but inhibited by Hoe 140. The stimulatory effect of des-Arg(10)-Lys-BK in 24-h experiments was inhibited by des-Arg(9)-[Leu(8)]-BK, des-Arg(10)-[Leu(9)]-Lys-BK and des-Arg(10)-[Hoe 140]. Similarly, the stimulatory effects of Sar[D-Phe(8)]-des-Arg(9)-BK and Tyr-Gly-Lys-Aca-Lys-des-Arg(9)-BK was inhibited by des-Arg(10)-[Hoe 140]. The following rank order of response was seen for inhibition of [3H]-BK binding to MG-63 cells: Lys-BK=BK=Hoe 140>>>>>>des-Arg(10)-Hoe 140=des-Arg(10)-Lys-BK=des-Arg(9)-BK=Tyr-Gly-Lys-Aca-Lys-des-Arg(9)-BK. Using [3H]-des-Arg(10)-Lys-BK, the following rank order of response for inhibition of binding was seen: des-Arg(10)-Lys-BK=Tyr-Gly-Lys-Aca-Lys-des-Arg(9)-BK>des-Arg(10)-Hoe 140>des-Arg(9)-BK=Lys-BK=BK=Hoe 140. MG-63 cells expressed mRNAs for BK B1 and B2 receptors, as assessed by RT-PCR. These data indicate that the human osteoblastic osteosarcoma cell line MG-63 is equipped with functional BK receptors of both B1 and B2 receptor subtypes. The B2 receptors are linked to a burst of prostanoid release, whereas the B1 receptors mediate a delayed prostaglandin response, indicating that the two receptor subtypes are linked to different signal transducing mechanisms or that the molecular mechanisms involved in prostaglandin release are different.

Binding, Competitive↗

PubMed2002

High extracellular calcium affects osteoclastogenesis in mouse bone marrow cell culture.

The effects of high extracellular calcium (high Ca) in the local microenvironment on osteoclasts, osteoclast progenitors and stromal cells are not fully understood. We examined high Ca effect on osteoclastogenesis in mouse bone marrow cell culture. Mouse bone marrow cells were cultured for up to 6 days in the medium supplemented with 1, 25(OH)2 vitamin D3 (D3). High Ca treatment at the early stage of culture (the initial 24 hours) reduced the number of tartrate resistant acid phosphatase-positive multinuclear cells (TRAP(+)MNCs). This treatment slightly up-regulated the mRNA expressions of receptor activator of NF-(B ligand (RANKL), RANK and osteoprotegerin (OPG). This inhibitory effect on the formation of TRAP(+)MNCs was recovered by RANKL. In contrast, high Ca treatment at the later stage of osteoclastogenesis (the last 2 days of culture) stimulated the formation of TRAP(+)MNCs, increased RANKL and RANK mRNA expressions and decreased OPG mRNA. High Ca at neither the early nor the later stage of culture affected the total number of adherent cells and the mRNA expression of alkaline phosphatase and osteopontin. In conclusion, high Ca affects osteoclastogenesis in a manner depending on the stage of osteoclastogenesis, which is partly mediated via the RANKL-RANK-OPG regulatory system.

Acid Phosphatase↗

PubMedDate not supplied

[Serotonin reuptake inhibitors may increase the risk of osteoporosis].

Remodelling of the skeleton is initiated by multinucleated osteoclasts resorbing either trabecular or cortical bone. Termination of the resorptive phase is followed by new bone formation by osteoblasts. Under normal conditions, remodeling is balanced and bone mass is preserved, with the amount of new bone formed equaling the amount that was initially resorbed. Skeletal remodeling is thought to be controlled by several hormones and many different cytokines. Recent studies have indicated that signaling molecules found in the nervous system may also play an important role in bone remodeling. One of these signaling molecules is thought to be serotonin (5-hydroxytryptamin; 5-HT). Osteoblasts and osteoclasts have receptors for serotonin and both cells express the membrane protein that is responsible for serotonin reuptake (5-HTT). Gene knockout studies in mice and use of selective serotonin reuptake inhibitors (SSRls) in mice and humans have suggested that inhibition of 5-HTT leads to reduced bone mass. These observations raise the possibility that patients treated with SSRIs may have an increased risk for secondary osteoporosis and skeletal fractures.

Animals↗

PubMedDate not supplied

[Bone remodeling].

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Anabolic Agents↗