The myokine irisin increases cortical bone mass Colaianni, Graziana; Cuscito, Concetta; Mongelli, Teresa ...
Proceedings of the National Academy of Sciences - PNAS,
09/2015, Letnik:
112, Številka:
39
Journal Article
Recenzirano
Odprti dostop
It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. ...Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 μg kg⁻¹. We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 μg kg⁻¹ per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes,OpnandSost,but notUcp1orPparγexpression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulatedAtf4, Runx2, Osx, Lrp5, β-catenin, Alp,andCol1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursorFndc5was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressedFndc5,albeit at low levels. Furthermore, muscle fibers from r-irisin–injected mice displayed enhanced Fndc5 positivity, and irisin inducedFdnc5mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle–bone connectivity.
We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant ...Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses.
The number and activity of osteoclasts (OCs) are critical for maintaining normal bone turnover. The number is determined by the rates of cell differentiation and death. TNF-related apoptosis-inducing ...ligand (TRAIL), a member of the TNF superfamily, induces apoptosis by interacting with its death receptors, (DR4, DR5). However, its activity can be modulated by two decoy receptors, (DcR1 and DcR2). In this paper we show that TRAIL treatment causes reduced OC viability as well as an increased apoptotic OC number. Loss of nuclei integrity and derangement of the actin microfilament were also induced by TRAIL in OCs. Moreover, we demonstrated the expression of all TRAIL receptors in both precursors and differentiated OCs, and the upregulation of DR5 during OC differentiation. Interestingly, DcR2 was upregulated in the early stage of osteoclastogenesis and downregulated at the end of the differentiation process. We showed that DR5, upregulated by TRAIL, could be the mediator of TRAIL-induced OC apoptosis, since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL. Furthermore, the intracellular pathway induced by TRAIL in OCs involves caspase-8 and Bid activation. In conclusion, our data highlight an important role for the TRAIL/TRAIL receptor system in the regulation of OC apoptosis.
Abstract Sclerostin, negative regulator of bone formation, has been originally known as an osteocyte product. Recently, it has been also detected in hypertrophic chondrocytes, distinctive cells of ...avascular cartilage which is invaded by capillaries and then replaced by vascularized bone. Thus, we hypothesized that sclerostin, in addition to its role already known, may exert an angiogenic activity. We first proved that sclerostin increased the proliferation of human umbilical vein endothelial cells (HUVECs), and next, by using the chicken chorioallantoic membrane (CAM) in vivo assay, we demonstrated that it exerts an angiogenic activity similar to that of vascular endothelial growth factor (VEGF). This last finding was reinforced by several in vitro approaches. Indeed, we showed that sclerostin induced the formation of a network of anastomosing tubules, a significant increase in the percentage of tubule number, total tubule length and number of junctions, as well as the ability of sclerostin-stimulated HUVECs to organize capillary-like structures and closed-meshes similar to VEGF. The angiogenic response elicited by the protein may be due to the binding to its receptor, LRP6, which is highly expressed at mRNA and protein levels by sclerostin treated HUVECs and through the production of two well-known pro-angiogenic cytokines, VEGF and placental growth factor (PlGF). Finally, we demonstrated that sclerostin was also responsible for the recruitment of osteoclasts and their circulating monocyte progenitors. Overall, these findings showed for the first time the new angiogenic in vitro role of sclerostin which could be also considered as a novel molecule in angiogenesis-osteogenesis coupling.
Impairment of Bone Remodeling in LIGHT/TNFSF14‐Deficient Mice Brunetti, Giacomina; Faienza, Maria Felicia; Colaianni, Graziana ...
Journal of bone and mineral research,
April 2018, 2018-04-00, 2018-04-01, 20180401, Letnik:
33, Številka:
4
Journal Article
Femoral and tibial tunnel widening (TW) after ACL reconstruction is a phenomenon increasing talk in the literature. It is underlying biological and mechanical causes.
The aim of this study was to ...evaluate the relationship between bone tunnel enlargement and two different ACL fixation systems.
40 patient underwent ACL reconstruction with hamstring; randomly divided into group A with 20 patients treated with stiff systems (femoral Rigidfix and tibial interference screw), and into group B, with 20 patients treated with morel elastic system (femoral and tibial Tight-rope). Evaluated postoperatively with knee MRI at 40 days, 3 months, 6 months to measure bone tunnel diameters widening.
At 40 days tunnel widening between two groups shows no statistically difference. At 3 months postoperatively, femoral bone tunnel widening amounted on average to 1.84 mm in middle of tunnel and 1 mm at the mouth in joint in group A, and respectively 3.2 mm and 2.5 mm in group B (p<0.05). Tibial tunnel widening was 1.24 mm at the mouth in joint and 1.3 mm in middle in group A and respectively 2.26 mm and 2.43 mm in group B (p<0.05). At 6 months femoral tunnel widening amounted on average to 2.45 mm in middle and 1.35 mm at the mouth in joint in group A and respectively 3.5 mm and 2.7 mm in group B (p<0.01). Tibial tunnel widening amounted on average to 1.27 at mouth in joint and 1 mm in middle of tunnel in group A and respectively 2.6 mm and 2.3 mm in group B (p<0.01).
This study results suggest elastic fixation system increases bone tunnel enlargement after ACL reconstruction with hamstring without correlation with worse clinical performance.
IV.
Although osteoclasts (OCs) differentiate under the control of RANK/RANKL/OPG system, a number of inflammatory cytokines can contribute to increase osteoclastogenesis in diseases associated with bone ...loss. Recently, different studies indicate that TRAIL is implicated in modulating osteoclastogenesis. Here, we investigated the effect of TRAIL on OC formation in physiological and pathological conditions with bone involvement utilizing osteoclastogenesis in vitro models represented by peripheral blood mononuclear cells (PBMCs) from healthy donors and patients affected by multiple myeloma or periodontal disease. We demonstrated that in PBMCs from healthy donors TRAIL can directly induce OC formation in the absence of RANKL, while exert an inhibitory effect when added concomitantly to RANKL. In PBMCs from the patients, in which media the levels of TRAIL, RANKL and OPG are elevated, the neutralization of TRAIL partially inhibits the OC formation, and this effect was reversed by RANKL addition. Finally, we detect high TRAIL levels in the sera from the patients. In conclusion, our results indicate that TRAIL could exert a different role in modulating OC differentiation in physiological and pathological conditions.
TRAIL Is Involved in Human Osteoclast Apoptosis BRUNETTI, GIACOMINA; ORANGER, ANGELA; MORI, GIORGIO ...
Annals of the New York Academy of Sciences,
November 2007, Letnik:
1116, Številka:
1
Journal Article
Recenzirano
: Control of osteoclast (OC) apoptosis has been recognized as a critical regulatory factor in bone remodeling. TRAIL, a member of the TNF superfamily, induces apoptosis in neoplastic and normal ...cells. However, few data are available on the effects of TRAIL on bone cells, thus in the present study we investigated TRAIL role on the apoptosis of human mature OCs. We show that TRAIL treatment causes reduced cell viability, loss of nuclei integrity, and derangement of the actin microfilament in OCs. We also demonstrated that the death receptor DR5, upregulated by TRAIL, could be the mediator of TRAIL‐induced OC apoptosis.
Abstract
Background
The viral load of asymptomatic SAR-COV-2 positive (ASAP) persons has been equal to that of symptomatic patients. On the other hand, there are no reports of ST-elevation myocardial ...infarction (STEMI) outcomes in ASAP patients. Therefore, we evaluated thrombus burden and thrombus viral load and their impact on microvascular bed perfusion in the infarct area (myocardial blush grade, MBG) in ASAP compared to SARS-COV-2 negative (SANE) STEMI patients.
Methods
This was an observational study of 46 ASAP, and 130 SANE patients admitted with confirmed STEMI treated with primary percutaneous coronary intervention and thrombus aspiration. The primary endpoints were thrombus dimension + thrombus viral load effects on MBG after PPCI. The secondary endpoints during hospitalization were major adverse cardiovascular events (MACEs). MACEs are defined as a composite of cardiovascular death, nonfatal acute AMI, and heart failure during hospitalization.
Results
In the study population, ASAP vs. SANE showed a significant greater use of GP IIb/IIIa inhibitors and of heparin (
p
< 0.05), and a higher thrombus grade 5 and thrombus dimensions (
p
< 0.05). Interestingly, ASAP vs. SANE patients had lower MBG and left ventricular function (
p
< 0.001), and 39 (84.9%) of ASAP patients had thrombus specimens positive for SARS-COV-2. After PPCI, a MBG 2–3 was present in only 26.1% of ASAP vs. 97.7% of SANE STEMI patients (
p
< 0.001). Notably, death and nonfatal AMI were higher in ASAP vs. SANE patients (
p
< 0.05). Finally, in ASAP STEMI patients the thrombus viral load was a significant determinant of thrombus dimension independently of risk factors (
p
< 0.005). Thus, multiple logistic regression analyses evidenced that thrombus SARS-CoV-2 infection and dimension were significant predictors of poorer MBG in STEMI patients. Intriguingly, in ASAP patients the female vs. male had higher thrombus viral load (15.53 ± 4.5 vs. 30.25 ± 5.51 CT;
p
< 0.001), and thrombus dimension (4.62 ± 0.44 vs 4.00 ± 1.28 mm
2
;
p
< 0.001). ASAP vs. SANE patients had a significantly lower in-hospital survival for MACE following PPCI (
p
< 0.001).
Conclusions
In ASAP patients presenting with STEMI, there is strong evidence towards higher thrombus viral load, dimension, and poorer MBG. These data support the need to reconsider ASAP status as a risk factor that may worsen STEMI outcomes.
PDF
