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Lerner, Ulf H.
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Publikasjoner (10 av 103) Visa alla publikasjoner
Persson, E., Souza, P. P. C., Floriano-Marcelino, T., Conaway, H. H., Henning, P. & Lerner, U. H. (2019). Activation of Shc1 Allows Oncostatin M to Induce RANKL and Osteoclast Formation More Effectively Than Leukemia Inhibitory Factor. Frontiers in Immunology, 10, Article ID 1164.
Åpne denne publikasjonen i ny fane eller vindu >>Activation of Shc1 Allows Oncostatin M to Induce RANKL and Osteoclast Formation More Effectively Than Leukemia Inhibitory Factor
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2019 (engelsk)Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, artikkel-id 1164Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background and Purpose: The gp130 family of cytokines signals through receptors dimerizing with the gp130 subunit. Downstream signaling typically activates STAT3 but also SHP2/Ras/MAPK pathways. Oncostatin M (OSM) is a unique cytokine in this family since the receptor (OSMR) activates a non-redundant signaling pathway by recruitment of the adapter Shc1. We have studied the functional relevance of Shc1 for OSM-induced bone resorption.

Experimental Approach: Osteoblasts were stimulated with OSM and STAT3 and Shc1 activations were studied using real-time PCR and Western blots. The role of STAT3 and Shc1 for OSM-induced RANKL expression and osteoclast formation was studied by silencing their mRNA expressions. Effects of OSM were compared to those of the closely related cytokine leukemia inhibitory factor (LIF).

Key Results: OSM, but not LIF, induced the mRNA and protein expression of Shc1 and activated phosphorylation of Shc1 in the osteoblasts. Silencing of Shc1 decreased OSM-induced activation of STAT3 and RANKL expression. Silencing of STAT3 had no effect on activation of Shc1, but prevented the OSM-mediated increase of RANKL expression. Silencing of either Shc1 or STAT3 in osteoblasts decreased formation of osteoclasts in OSM-stimulated co-cultures of osteoblasts and macrophages. In agreement with these observations, OSM was a more potent and robust stimulator than LIF of RANKL formation and bone resorption in mouse calvariae and osteoclast formation in bone marrow cultures.

Conclusions and Implications: Activation of the Shc1-dependent STAT3 signaling is crucial for OSM-induced osteoclast formation. Inhibition of Shc1 is a potential mechanism to specifically inhibit OSM-induced bone resorption.

sted, utgiver, år, opplag, sider
Frontiers Media S.A., 2019
Emneord
OSM, LIF, RANKL, Shc1, osteoclast, bone resorption
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-159851 (URN)10.3389/fimmu.2019.01164 (DOI)000469268500001 ()
Forskningsfinansiär
Swedish Research CouncilSwedish Rheumatism AssociationKing Gustaf V Jubilee FundVästerbotten County Council
Tilgjengelig fra: 2019-06-11 Laget: 2019-06-11 Sist oppdatert: 2019-06-11bibliografisk kontrollert
Souza, P. P. C., Lundberg, P., Lundgren, I., Magalhäes, F. A. C., Costa-Neto, C. M. & Lerner, U. H. (2019). Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva. Scientific Reports, 9, Article ID 2973.
Åpne denne publikasjonen i ny fane eller vindu >>Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva
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2019 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 2973Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B1 and B2 receptor expression in human gingival fibroblasts and in mouse gingiva. Both P. gingivalis LPS and the synthetic TLR2 agonist Pam2CSK4 increased kinin receptor transcripts. Silencing of TLR2, but not of TLR4, inhibited the induction of kinin receptor transcripts by both P. gingivalis LPS and Pam2CSK4. Human gingival fibroblasts (HGF) exposed to Pam2CSK4 increased binding sites for bradykinin (BK, B2receptor agonist) and des-Arg10-Lys-bradykinin (DALBK, B1 receptor agonist). Pre-treatment of HGF for 24 h with Pam2CSK4 resulted in increased PGE2 release in response to BK and DALBK. The increase of B1 and B2 receptor transcripts by P. gingivalis LPS was not blocked by IL-1β neutralizing antibody; TNF-α blocking antibody did not affect Breceptor up-regulation, but partially blocked increase of B2 receptor mRNA. Injection of P. gingivalis LPS in mouse gingiva induced an increase of B1 and B2 receptor mRNA. These data show that activation of TLR2 in human gingival fibroblasts as well as in mouse gingival tissue leads to increase of B1 and B2 receptor mRNA and protein.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2019
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-157584 (URN)10.1038/s41598-018-37777-z (DOI)000459799800122 ()30814538 (PubMedID)
Tilgjengelig fra: 2019-04-01 Laget: 2019-04-01 Sist oppdatert: 2019-04-01bibliografisk kontrollert
Conaway, H. H., Henning, P., Lie, A., Tuckermann, J. & Lerner, U. H. (2019). Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D3 and parathyroid hormone–induced osteoclastogenesis. The FASEB Journal, 33(12), 14394-14409
Åpne denne publikasjonen i ny fane eller vindu >>Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D3 and parathyroid hormone–induced osteoclastogenesis
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2019 (engelsk)Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, nr 12, s. 14394-14409Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Glucocorticoid (GC) therapy decreases bone mass and increases the risk of fractures. We investigated interactions between the GC dexamethasone (DEX) and the bone resorptive agents 1,25(OH)2-vitamin D3 (D3) and parathyroid hormone (PTH) on osteoclastogenesis. We observed a synergistic potentiation of osteoclast progenitor cell differentiation and formation of osteoclasts when DEX was added to either D3- or PTH-treated mouse bone marrow cell (BMC) cultures. Cotreatment of DEX with D3 or PTH increased gene encoding calcitonin receptor (Calcr), acid phosphatase 5, tartrate resistant (Acp5), cathepsin K (Ctsk), and TNF superfamily member 11 (Tnfsf11) mRNA, receptor activator of NF-κB ligand protein (RANKL), numbers of osteoclasts on plastic, and pit formation and release of C-terminal fragment of type I collagen from cells cultured on bone slices. Enhanced RANKL protein expression caused by D3 and DEX was absent in BMC from mice in which the GC receptor (GR) was deleted in stromal cells/osteoblasts. Synergistic interactions between DEX and D3 on RANKL and osteoclast formation were present in BMC from mice with attenuated GR dimerization. These data demonstrate that the GR cooperates with D3 and PTH signaling, causing massive osteoclastogenesis, which may explain the rapid bone loss observed with high dosages of GC treatment.

sted, utgiver, år, opplag, sider
Federation Amer Soc Exp Biol, 2019
Emneord
osteoporosis, bone resorption, calcium-regulating hormones, osteoclasts
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-167633 (URN)10.1096/fj.201802729RRR (DOI)000507466100103 ()31675485 (PubMedID)2-s2.0-85076062407 (Scopus ID)
Tilgjengelig fra: 2020-02-03 Laget: 2020-02-03 Sist oppdatert: 2020-02-03bibliografisk kontrollert
Lerner, U. H., Kindstedt, E. & Lundberg, P. (2019). The critical interplay between bone resorbing and bone forming cells. Journal of Clinical Periodontology, 46, 33-51
Åpne denne publikasjonen i ny fane eller vindu >>The critical interplay between bone resorbing and bone forming cells
2019 (engelsk)Inngår i: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 46, s. 33-51Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aim: In this article, the interplay between bone resorbing and bone forming cells is reviewed.

Method: This review examines the comprehensive literature on the interaction between bone resorption and bone formation.

Results: Coupling between bone resorption and bone formation refers to the process within basic multicellular units, in which osteoclastic bone resorption is met by the differentiation of osteoblasts and their bone forming activity. There are many possible signalling molecules that contribute to coupling at the asynchronously working remodelling sites throughout our skeleton. These include growth factors released from the bone matrix during bone resorption, soluble and membrane products of the osteoclasts and their precursors and signals from osteocytes.

Conclusions: In this review, we describe the potential roles of a number of these factors, whose interactions are essential for a tight control of coupling within individual remodelling units, in order to control skeletal mass. Both pre‐clinical evidence and clinical evidence pinpoint that molecules in the WNT signalling pathway could be promising bone augmentation therapeutic targets. Regarding oral implications, there is support, from preclinical studies in rats, that anti‐sclerostin antibodies can restore alveolar bone mass.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-161525 (URN)10.1111/jcpe.13051 (DOI)000472200500003 ()30623989 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilVästerbotten County CouncilSwedish Rheumatism Association
Tilgjengelig fra: 2019-07-11 Laget: 2019-07-11 Sist oppdatert: 2019-07-11bibliografisk kontrollert
Nordstrand, A., Bovinder Ylitalo, E., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity. International Journal of Molecular Sciences, 19(4), Article ID 1223.
Åpne denne publikasjonen i ny fane eller vindu >>Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
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2018 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 4, artikkel-id 1223Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

sted, utgiver, år, opplag, sider
MDPI, 2018
Emneord
prostate cancer, bone, metastasis, androgen receptor, osteoblast, osteoclast, BMP
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-146973 (URN)10.3390/ijms19041223 (DOI)000434978700302 ()29670000 (PubMedID)2-s2.0-85045938451 (Scopus ID)
Tilgjengelig fra: 2018-04-24 Laget: 2018-04-24 Sist oppdatert: 2018-11-21bibliografisk kontrollert
Bovinder Ylitalo, E., Nordstrand, A., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 50-50
Åpne denne publikasjonen i ny fane eller vindu >>Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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2018 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 50-50Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
American Association for Cancer Research, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-151399 (URN)000441803800065 ()
Konferanse
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Merknad

Supplement: S, Meeting Abstract: A048

Tilgjengelig fra: 2018-09-05 Laget: 2018-09-05 Sist oppdatert: 2018-09-05bibliografisk kontrollert
Strålberg, F., Kassem, A., Kasprzykowski, F., Abrahamson, M., Grubb, A., Lindholm, C. & Lerner, U. H. (2017). Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vitro and in vivo by cysteine proteinase inhibitors. Journal of Leukocyte Biology, 101(5), 1233-1243
Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vitro and in vivo by cysteine proteinase inhibitors
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2017 (engelsk)Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, nr 5, s. 1233-1243Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginylleucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-kappa B ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors. Adult mice were injected locally with LPS and then treated with E-64 and osteoclast formation assessed by the number of cathepsin K+ multinucleated cells. Cystatin C inhibited LPS-induced osteoclast formation time and concentration dependently (IC50 = 0.3 mu M). The effect was associated with decreased mRNA and protein expression of tartrate-resistant acid phosphatase (TRAP) and cathepsin K and of the osteoclastogenic transcription factors c-Fos and NFATc1. LPS-induced osteoclast formation on bone slices was also inhibited by cystatin C, resulting in decreased pit formation and release of bone matrix proteins. Similar data were obtained with E-64 and Z-RLVG-CHN2. Cystatin C was internalized in BMMs stimulated by LPS but not in unstimulated BMMs. Osteoclast formation induced by LPS was dependent on TNF-alpha, and the 3 inhibitors abolished LPS-induced TNF superfamily 2 (gene encoding TNF-alpha; Tnfsf2) mRNA expression without affecting Il1b, Il6, or oncostatin M (Osm) expression. Formation of osteoclasts in the skull bones after local LPS stimulation was inhibited by E-64. It is concluded that cysteine proteinase inhibitors effectively inhibit LPS-induced osteoclast formation in vivo and in vitro by inhibition of TNF-alpha expression. The targeting of cysteine proteinases might represent a novel treatment modality for prevention of inflammatory bone loss.

sted, utgiver, år, opplag, sider
FEDERATION AMER SOC EXP BIOL, 2017
Emneord
inflammation, cystatin C, macrophages, periodontitis, rheumatoid arthritis
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-136068 (URN)10.1189/jlb.3A1016-433R (DOI)000401430100021 ()28196851 (PubMedID)
Tilgjengelig fra: 2017-06-16 Laget: 2017-06-16 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Nordstrand, A., Halin Bergström, S., Thysell, E., Bovinder-Ylitalo, E., Lerner, U. H., Widmark, A., . . . Wikström, P. (2017). Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone. Clinical and Experimental Metastasis, 34(3-4), 261-271
Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone
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2017 (engelsk)Inngår i: Clinical and Experimental Metastasis, ISSN 0262-0898, E-ISSN 1573-7276, Vol. 34, nr 3-4, s. 261-271Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.

sted, utgiver, år, opplag, sider
Springer, 2017
Emneord
Bone metastasis, IGF-1R, Apoptosis, Proliferation, Immune response, RUNX2, TRAP
HSV kategori
Forskningsprogram
onkologi
Identifikatorer
urn:nbn:se:umu:diva-131804 (URN)10.1007/s10585-017-9848-8 (DOI)000401996600008 ()28447314 (PubMedID)
Merknad

Special Issue.

Originally published in thesis in manuscript form.

Tilgjengelig fra: 2017-02-22 Laget: 2017-02-22 Sist oppdatert: 2019-05-20bibliografisk kontrollert
Stattin, E.-L., Henning, P., Klar, J., McDermott, E., Stecksen-Blicks, C., Sandström, P.-E., . . . Lerner, U. H. (2017). SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. Scientific Reports, 7, Article ID 3012.
Åpne denne publikasjonen i ny fane eller vindu >>SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
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2017 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 3012Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2017
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-136033 (URN)10.1038/s41598-017-02533-2 (DOI)000402879800068 ()28592808 (PubMedID)
Tilgjengelig fra: 2017-06-13 Laget: 2017-06-13 Sist oppdatert: 2018-08-31bibliografisk kontrollert
Conaway, H. H., Henning, P., Lie, A., Tuckermann, J. & Lerner, U. H. (2016). Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity. Bone, 93, 43-54
Åpne denne publikasjonen i ny fane eller vindu >>Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity
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2016 (engelsk)Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 93, s. 43-54Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Glucocorticoid (GC) therapy is the greatest risk factor for secondary osteoporosis. Pathogenic mechanisms involve an initial increase in bone resorption followed by decreased bone formation. To gain a better understanding of the resorptive activity of GCs, we have used mouse bone marrow macrophages (BMM) to determine if GCs can directly modulate RANKL stimulated osteoclast formation and/or activity. In agreement with previous studies, experiments performed in plastic wells showed that GCs (dexamethasone, hydrocortisone, and prednisolone) inhibited osteoclast number and size during the initial phases of RANKL stimulated osteoclastogenesis; however, in prolonged cultures, decreased apoptosis was observed and escape from GC induced inhibition occurred with an enhanced number of osteoclasts formed, many with an increased area. When BMM cells were seeded on bone slices, GCs robustly enhanced RANKL stimulated formation of resorption pits and release of CTX without affecting the number or size of osteoclasts formed and with no effect on apoptosis. Stimulation of pit formation was not associated with increased life span of osteoclasts or an effect on mRNA expression of several osteoclastic or osteoclastogenic genes. The potentiation of RANKL induced CTX release by dexamethasone was significantly less in BMM cells from mice with conditional knockout of the osteoclastic glucocorticoid receptor and completely absent in cells from Gem mice, which carry a point mutation in one dimerizing interface of the GC receptor. These data suggest that: 1. Plastic is a poor medium to use for studying direct effects of GCs on osteoclasts 2. GCs can enhance bone resorption without decreasing apoptosis, and 3. A direct enhancement of RANKL mediated resorption is stimulated by the dimeric GC -receptor.

Emneord
Glucocorticoid, Glucocorticoid receptor, Osteoclast, Bone resorption, Osteoporosis
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-129802 (URN)10.1016/j.bone.2016.08.024 (DOI)000386987500005 ()27596806 (PubMedID)
Tilgjengelig fra: 2017-01-09 Laget: 2017-01-09 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Organisasjoner