Coupling during bone remodeling refers to the spatial and temporal coordination of bone resorption with bone formation. Studies have assessed the subtle interactions between osteoclasts and ...osteoblasts to preserve bone balance. Traditionally, coupling research related to osteoclast function has focused on bone resorption activity causing the release of growth factors embedded in the bone matrix. However, considerable evidence from in vitro, animal, and human studies indicates the importance of the osteoclasts themselves in coupling phenomena, and many osteoclast-derived coupling factors have been identified. These include sphingosine-1-phosphate, vesicular–receptor activator of nuclear factor-κB, collagen triple helix repeat containing 1, and cardiotrophin-1. Interestingly, neuronal guidance molecules, such as slit guidance ligand 3, semaphorin (SEMA) 3A, SEMA4D, and netrin-1, originally identified as instructive cues allowing the navigation of growing axons to their targets, have been shown to be involved in the intercellular cross-talk among bone cells. This review discusses osteoclast–osteoblast coupling signals, including recent advances and the potential roles of these signals as therapeutic targets for osteoporosis and as biomarkers predicting human bone health.
Abstract
Context
Studies in aged mice support a role for kynurenine, a tryptophan metabolite, in age-induced bone loss; however, the role of kynurenine in human bone metabolism is not well ...understood.
Objective
To assess whether the kynurenine level in bone marrow (BM) aspirates, directly reflecting the bone microenvironment, is associated with osteoporosis-related phenotypes and bone biochemical markers.
Design and Setting
A case-control study conducted in a clinical unit.
Participants and Main Outcome Measures
BM samples were collected from 72 patients at the time of hip surgery for either fragility hip fracture (HF) (n = 27) or for other causes (n = 45). In these samples, kynurenine was measured by liquid chromatography–tandem mass spectrometry, and the levels of tartrate-resistant acid phosphatase 5b (TRAP5b), bone-specific alkaline phosphatase (BSALP), receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) were measured by immunoassay.
Results
Age was positively correlated with BM kynurenine level. After adjustment for confounders, subjects with fragility HF had a 39.7% higher BM kynurenine level than those without, and the OR per SD increment in BM kynurenine level for fragility HF was 3.80. The BM kynurenine level was inversely associated with bone mass at the total femur. Higher kynurenine concentrations were significantly associated with higher TRAP-5b and RANKL levels, but not with BSALP and OPG levels, in BM plasma.
Conclusion
These results suggest that increased kynurenine levels during aging may contribute to the bone fragility seen in the elderly through increased bone resorption, with a resultant imbalance in bone remodeling.
Increased kynurenine levels during aging may contribute to the bone fragility seen in the elderly through the stimulation of bone resorption, with a resultant imbalance in bone remodeling.
Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms ...underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and
knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in
KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis.
The Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) was proposed for predicting the metastatic potential of pheochromocytoma and paraganglioma to overcome the limitations of the ...Pheochromocytoma of the Adrenal Scaled Score (PASS). However, to date, no study validating the GAPP has been conducted, and previous studies did not include mutations in the succinate dehydrogenase type B (SDHB) gene in the score calculation. In this retrospective cohort study, we validated the prediction ability of GAPP and assessed whether it would be improved by inclusion of the loss of SDHB immunohistochemical staining.
We divided the tumors into non-metastatic and metastatic groups based on the presence of synchronous or metachronous metastases. The GAPP score and PASS at the initial operation were measured. Moreover, we combined some GAPP parameters with the immunohistochemical staining of SDHB to obtain a modified GAPP (M-GAPP) score.
Metastasis occurred in 15/72 (20.8%) patients, with a mean follow-up of 43.5 months. Loss of SDHB staining was more frequent (P = 0.044) in the metastatic group. The GAPP score (P = 0.006), PASS (P = 0.003), and M-GAPP score (P<0.001) were all higher in the metastatic group. Twelve of 40 (30.0%) moderately or poorly differentiated tumors, as defined by the GAPP score, and 12/34 (35.3%) tumors with a PASS ≥4 were metastatic. Conversely, 10/19 (52.6%) tumors with an M-GAPP score ≥3 were metastatic. The area under the curve of the M-GAPP score (0.822) was significantly higher than that of the GAPP (0.728) (P = 0.012), but similar to that of the PASS (0.753) (P = 0.411). The GAPP (P = 0.032) and M-GAPP scores (P = 0.040), but not PASS (P = 0.200), negatively correlated with metastasis-free survival.
The GAPP was validated, and M-GAPP, a combination of some GAPP parameters and loss of SDHB staining, might be useful for the prediction of the metastatic potential of pheochromocytoma and paraganglioma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An adrenal incidentaloma is an adrenal mass found in an imaging study performed for other reasons unrelated to adrenal disease and often accompanied by obesity, diabetes, or hypertension. The ...prevalence and incidence of adrenal incidentaloma increase with age and are also expected to rise due to the rapid development of imaging technology and frequent imaging studies. The Korean Endocrine Society is promoting an appropriate practice guideline to meet the rising incidence of adrenal incidentaloma, in cooperation with the Korean Adrenal Gland and Endocrine Hypertension Study Group. In this paper, we discuss important core issues in managing the patients with adrenal incidentaloma. After evaluating core proposition, we propose the most critical 20 recommendations from the initially organized 47 recommendations by Delphi technique.
A highly conductive polymer layer coated on a microstructured indium tin oxide (ITO) electrode is proposed as a simple way to enhance outcoupling in organic light‐emitting diodes. The relatively low ...refractive index of the conductive polymer provides an index contrast between the organic and ITO layers so that structuring of ITO electrodes can result in a significant optical effect.
Background
The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%–20%. Although there are indicators to assess metastatic risks, none of them predict metastasis ...reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL.
Methods
In the cross‐sectional cohort (n = 180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra‐adrenal location, and secretory type (ASES) score in the longitudinal cohort (n = 114).
Results
In the cross‐sectional cohort, pseudohypoxia group‐related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16 nmol/L, and tumor size >6.0 cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval CI: 0.738–0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567–0.814, p = 0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio = 25.07, 95% CI: 5.65–111.20). A GMS score ≥2 (p < 0.001), but not ASES score ≥2 (p = 0.090), was associated with shorter progression‐free survival.
Conclusion
The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL.
Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical ...roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.
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