Soluble RANKL exaggerates hindlimb suspension-induced osteopenia but not muscle protein balance

ABSTRACTWe examined the hypothesis that exaggerating unloading-induced bone loss using a combination of hindlimb suspension (HLS) and exogenous injections of receptor activator of nuclear factor kappa-B ligand (RANKL) also exaggerates muscle loss. Forty, male C57Bl/6J mice (16 weeks) were subjected to HLS or normal ambulation (ground control, GC) for 14 days. Mice received 3 intraperitoneal injections of either human recombinant soluble RANKL or PBS as control (n=10/group) at 24 hour intervals starting on Day 1 of HLS. GC + RANKL and HLS mice exhibited similar decreases in trabecular bone volume and density in both proximal tibias and distal femurs. However, RANKL affected trabecular number, separation, and connectivity density, while HLS decreased trabecular thickness. The combination of RANKL and HLS exacerbated these changes. Similarly, GC + RANKL and HLS mice saw comparable decreases in cortical bone volume, thickness, and strength in femur midshafts, and combination treatment exacerbated these changes. Plasma concentrations of P1NP were increased in both groups receiving RANKL, while CTX concentrations were unchanged. HLS decreased gastrocnemius weight and was associated with a reduction in global protein synthesis, and no change in proteasome activity. This change was correlated with a decrease in S6K1 and S6 phosphorylation, but no change in 4E-BP1 phosphorylation. Injection of RANKL did not alter muscle protein metabolism in GC or HLS mice. Our results suggest that injection of soluble RANKL exacerbates unloading-induced bone loss, but not unloading-induced muscle loss. This implies a temporal disconnect between muscle and bone loss in response to unloading.

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Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice

Journal of Osteoporosis ◽

10.4061/2010/157323 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6

Author(s):

Zelieann R. Craig ◽

Samuel L. Marion ◽

Janet L. Funk ◽

Mary L. Bouxsein ◽

Patricia B. Hoyer

Keyword(s):

Bone Loss ◽

Volume Fraction ◽

Ovarian Tissue ◽

Ovarian Failure ◽

Bone Volume ◽

Bone Volume Fraction ◽

Trabecular Thickness ◽

Ct Analysis ◽

Time Point ◽

Young Mice

Previous work showed that retaining residual ovarian tissue protects young mice from accelerated bone loss following ovarian failure. The present study was designed to determine whether this protection is also present in aged animals. Aged (9–12 months) C57BL/6Hsd female mice were divided into: CON (vehicle), VCD (160 mg/kg; 15d), or OVX (ovariectomized). Lumbar BMD was monitored by DXA andμCT used to assess vertebral microarchitecture. BMD was not different between VCD and CON at any time point but was lower (P<.05) than baseline, starting 1 month after ovarian failure in VCD and OVX mice. FollowingμCT analysis there were no differences between CON and VCD, but OVX mice had lower bone volume fraction, trabecular thickness, and a trend for decreased connectivity density. These findings provide evidence that retention of residual ovarian tissue may protect aged follicle-depleted mice from accelerated bone loss to a lesser extent than that observed in young mice.

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Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.5.e928 ◽

1992 ◽

Vol 263 (5) ◽

pp. E928-E934 ◽

Cited By ~ 50

Author(s):

K. S. Nair ◽

R. G. Schwartz ◽

S. Welle

Keyword(s):

Amino Acids ◽

Protein Degradation ◽

Protein Metabolism ◽

Muscle Protein ◽

Plasma Concentrations ◽

Essential Amino Acids ◽

Whole Body ◽

Skeletal Muscle Protein ◽

Muscle Protein Metabolism

Leucine has been proposed as an in vivo regulator of protein metabolism, although the evidence for this in humans remains inconclusive. To test this hypothesis, we infused either L-leucine (154 +/- 1 mumol.kg-1 x h-1) or saline intravenously in six healthy men in two separate studies. L-Leucine infusion increased plasma concentrations of leucine and alpha-ketoisocaproate from 112 +/- 6 and 38 +/- 3 mumol/l to 480 +/- 27 (P < 0.001) and 94 +/- 13 mumol/l (P < 0.001), respectively, without any significant change in circulating insulin or C peptide levels. Leucine infusion decreased plasma concentrations of several amino acids and decreased whole body valine flux and valine oxidation (using L-[1-13C]valine as a tracer) and phenylalanine flux (using [2H5]-phenylalanine as a tracer). According to arteriovenous differences across the leg, the net balance of phenylalanine, valine, and lysine shifted toward greater retention during leucine infusion, whereas alanine balance did not change. Valine release and phenylalanine release from the leg (estimated from the dilution of respective tracers) decreased, indicating inhibition of protein degradation by leucine infusion. We conclude that leucine decreases protein degradation in humans and that this decreased protein degradation during leucine infusion contributes to the decrease in plasma essential amino acids. This study suggests a potential role for leucine as a regulator of protein metabolism in humans.

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5 alpha-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.6.e853 ◽

1994 ◽

Vol 267 (6) ◽

pp. E853-E859 ◽

Cited By ~ 6

Author(s):

J. H. Tobias ◽

A. Gallagher ◽

T. J. Chambers

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Cancellous Bone ◽

Bone Growth ◽

Bone Volume ◽

Ovariectomized Rats ◽

Trabecular Thickness ◽

Longitudinal Bone Growth ◽

Periosteal Bone Formation

Although androgens are thought to be important for skeletal maintenance in females and males, little is known about the mechanisms involved. To investigate this question further, we examined the effects of administering 0.01, 0.1, or 1.0 mg/kg 5 alpha-dihydrotestosterone (DHT) for 60 days on the skeleton of ovariectomized rats. Treatment was delayed until 90 days after ovariectomy to enable bone loss to stabilize. We found that ovariectomy markedly reduced cancellous bone volume of the proximal tibial metaphysis due to a combination of loss and thinning of trabeculae. Cancellous bone volume was partially restored by all doses of DHT, with trabecular thickness, but not number, returning to that of sham-operated animals. DHT also stimulated longitudinal bone growth and endosteal and periosteal bone formation and suppressed histomorphometric indexes of cancellous bone resorption. This suggests that DHT influences skeletal metabolism in osteopenic ovariectomized rats both by stimulating bone formation and suppressing resorption, although it is unclear which, if any, of these actions predominate at cancellous sites.

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Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00111.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1406-E1417 ◽

Cited By ~ 13

Author(s):

Kanogwun Thongchote ◽

Saovaros Svasti ◽

Jarinthorn Teerapornpuntakit ◽

Nateetip Krishnamra ◽

Narattaphol Charoenphandhu

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Trabecular Bone ◽

Elevated Serum ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Mineral Density ◽

Trabecular Thickness ◽

Running Exercise

A marked decrease in β-globin production led to β-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous β-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1–2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1α and -1β. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in β-thalassemia.

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Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Journal of Endocrinology ◽

10.1677/joe.0.1630015 ◽

1999 ◽

Vol 163 (1) ◽

pp. 15-24 ◽

Cited By ~ 23

Author(s):

T Vary ◽

D Dardevet ◽

J Grizard ◽

L Voisin ◽

C Buffiere ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Protein Degradation ◽

Muscle Protein ◽

Plasma Concentrations ◽

Skeletal Muscle Protein ◽

Muscle Protein Metabolism ◽

Protein Synthesis And Degradation ◽

Synthesis And Degradation

We investigated the ability of pentoxifylline (PTX) to modulate protein synthesis and degradation in the presence and absence of insulin during incubation of epitrochlearis muscle, 2 or 6 days after injection of Escherichia coli. On days 2 and 6 after infection, protein synthesis was inhibited by 25%, whereas proteolysis was enhanced by 75%. Insulin (2 nM) in vitro stimulated protein synthesis in muscles from infected rats to the same extent as in controls. The ability of insulin to limit protein degradation was severely blunted 48 h after infection. On day 6 after infection, insulin inhibited proteolysis to a greater extent than on day 2. PTX suppressed the increase in plasma concentrations of tumor necrosis factor more than 600-fold after injection of bacteria, and partially prevented the inhibition of protein synthesis and stimulation of protein degradation during sepsis. Moreover, PTX administration maintained the responsiveness of protein degradation to insulin during sepsis. Thus cytokines may influence skeletal muscle protein metabolism during sepsis, both indirectly through inhibition of the effects of insulin on proteolysis, and directly on the protein synthesis and degradation machinery.

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AB0099 IN VIVO BONE MICROARCHITECTURE ANALYSIS IN A PSORIATIC ARTHRITIC PATIENT BEFORE AND AFTER ANTI-TNFΑ TREATMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.47 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1078.3-1078

Author(s):

E. Soldati ◽

L. Escoffier ◽

S. Gabrie ◽

J. P. Mattei ◽

S. Camilleri ◽

...

Keyword(s):

Bone Loss ◽

Volume Fraction ◽

Bone Microarchitecture ◽

Bone Volume ◽

Normal Range ◽

Bone Volume Fraction ◽

Trabecular Thickness ◽

Posterior Tibial ◽

Before And After

Background:In psoriatic arthritis (PA), a systemic inflammatory phenomenon, mainly mediated by TNFα, is characterized by a bone loss due to osteoclastic stimulation. Anti-TNFα treatment should inhibit this phenomenon having a role on systemic bone loss. Ultra-high field MRI (UHF MRI) may be a tool of choice for the quantification of bone microarchitecture (BM) in vivo.Objectives:The purpose of the present study was to quantify BM using UHF MRI in a PA patient and to follow up changes related to anti-TNFα treatment.Methods:An 18 years-old untreated PA patient with knee arthritis and 7 gender-matched healthy controls [21.6±0.8 years] were scanned using a gradient echo sequence at UHF MRI (TR/TE = 15/4.36ms). After a year of Adalimumab treatment, the patient underwent a second UHF MRI. BM analysis was performed on sagittal planes in regions corresponding to tendon insertion: proximal and distal patellar, and posterior tibial. A PET-FNa imaging was also performed before and after treatment. BM was characterized using the bone volume fraction (BVF), the trabecular thickness (TbTh) and the spacing (TbSp) and number of trabeculae (TbN). Student T-test was used for the statistical analysis and a p-value < 0.01 was considered as significative.Results:PET-FNa recorded before the treatment illustrated hypermetabolic areas which resumed after the treatment while the patient was in remission. The BM parameters are shown in figure 1. The BM parameters quantified before the treatment were very different as compared to controls. BVF was significatively lower (-33±23%), TbSp and TbN were significatively distinct (-27±3% and +27±9%) for all ROIs but proximal patellar, while TbTh was in the normal range (-2±2%). After 1 year of treatment, BM parameters were significantly improved. BVF was no longer different than controls (-8±6%). Similarly, TbSp and TbN were in the normal range (+13±12% and -15±10%) for all ROIs but posterior tibial. TbTh (-5±3%) was only significantly decreased for the distal patella.Table 1. Data are presented as mean ± SD. “P.” refers as patient. BVF: Bone volume fraction, TbTh: Trabecular Thickness, TbSp: Trabecular Space, TbN: Trabecular number. * indicates a statistically significant difference (p < 0.01) with the Healthy reference values.Conclusion:Our results illustrated knee microstructure alterations in a PA patient and a normalization after a year of treatment. The abnormalities initially observed were not only localized in the hypermetabolic regions identified by PET-FNa, suggesting that the bone loss was global and not related to inflammatory sites.Using UHF MRI, we highlighted and quantified in vivo BM anomalies in a patient with an inflammatory rheumatism together with the reversibility after one year of treatment.Acknowledgements:All the authors declare no conflict of interest.ES has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skodowska-Curie grant agreement No713750. Also, it has been carried out with the financial support of the Regional Council of Provence- Alpes-Côte d’Azur and with the financial support of the A*MIDEX (n° ANR- 11-IDEX-0001-02), funded by the “Investissements d’Avenir” project funded by the French Government, managed by the French National Research Agency (ANR). edgements to declare.Disclosure of Interests:None declared

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The effects of ovarian transplantation on bone loss in ovariectomized rats

Journal of Endocrinology ◽

10.1677/joe.0.1420187 ◽

1994 ◽

Vol 142 (1) ◽

pp. 187-192 ◽

Cited By ~ 5

Author(s):

J H Tobias ◽

T J Chambers ◽

A Gallagher

Keyword(s):

Bone Loss ◽

Cancellous Bone ◽

Ovarian Function ◽

Hormone Replacement ◽

Bone Volume ◽

Ovariectomized Rats ◽

Vaginal Smears ◽

Trabecular Thickness ◽

Ovarian Transplantation ◽

Trabecular Number

Abstract Although hormone replacement therapy can prevent postmenopausal bone loss, it does not restore bone mass to normal in patients with established osteoporosis. This might reflect a failure to reproduce certain aspects of gonadal function. One method of investigating this possibility would be to examine the effect of ovarian transplantation on the skeleton of osteopaenic ovariectomized rats. However, ovarian transplantation may not fully restore ovarian function to normal, and it is not known whether transplanted ovaries reproduce the action of native ovaries on the skeleton. Therefore, we investigated whether renal capsular or subcutaneous ovarian transplants prevent the effects of ovariectomy on histomorphometric indices of rat tibiae over 44 days. Daily vaginal smears showed that oestrous cycles returned in all but two of 25 animals receiving ovarian transplants. We found that ovarian transplantation prevented the reduction in cancellous bone volume following ovariectomy. While trabecular number was reduced in ovariectomized animals receiving renal capsular ovarian transplants compared to intact animals, trabecular thickness was increased in both transplant groups. Ovarian transplantation also prevented the increase in cancellous and cortical bone formation, cancellous bone resorption and longitudinal growth rate caused by ovariectomy. We conclude that restoration of ovarian function by ovarian transplantation largely prevents the effects of ovariectomy on histomorphometric indices of rat tibiae, suggesting that transplanted ovaries can substitute for the action of native ovaries on the skeleton. Journal of Endocrinology (1994) 142, 187–192

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Salmon calcitonin reduces vertebral bone loss in glucocorticoid-treated beagles

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.6.e938 ◽

1993 ◽

Vol 264 (6) ◽

pp. E938-E942 ◽

Cited By ~ 3

Author(s):

K. W. Lyles ◽

T. W. Jackson ◽

T. Nesbitt ◽

L. D. Quarles

Keyword(s):

Bone Loss ◽

Bone Mass ◽

Trabecular Bone ◽

Salmon Calcitonin ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Trabecular Thickness ◽

Vertebral Bone ◽

X Ray ◽

Calcitonin Treatment

Glucocorticoids induce bone loss by increasing bone resorption and decreasing bone formation. In this study we have investigated the potential of salmon calcitonin to attenuate glucocorticoid-induced bone loss in a dog model. Male beagles were divided into three groups: 1) untreated controls, 2) prednisone-treated dogs (1 mg.kg-1.day-1 orally), and 3) prednisone-calcitonin-treated dogs (1.5 U.kg-1.day-1 calcitonin subcutaneously and 1 mg.kg-1.day-1 prednisone orally). Assessment of bone mass by dual energy X-ray absorptiometry demonstrated that bone density remained stable in controls throughout 48 wk. Prednisone-treated dogs lost 13.2% of their initial bone mass by 48 wk. Concomitant calcitonin treatment attenuated prednisone-induced bone loss to only 3.2% at 48 wk. Bone histomorphometry of the spine showed reduced trabecular bone volume in prednisone-treated dogs, whereas control and prednisone-calcitonin-treated animals maintained normal trabecular bone volume. Both prednisone- and prednisone-calcitonin-treated dogs acquired a defect in osteoblastic function as evidenced by a reduction in mean wall thickness and trabecular thickness. Thus calcitonin attenuates the early bone loss induced by glucocorticoids. However, calcitonin failed to prevent glucocorticoid-induced osteoblast dysfunction.

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