Significance of ZO-1, an Intercellular Adhesion Molecule, as a Prognostic Marker in Lung Adenocarcinoma.

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker.

Denosumab Improves Glomerular Filtration Rate in Osteoporotic Patients With Normal Kidney Function by Lowering Serum Phosphorus.

Higher serum phosphorus (Pi) increases the risk for chronic kidney disease (CKD). It was reported that a single administration of denosumab or zoledronate significantly suppressed serum Pi levels as well as those of bone resorption markers in serum. Also, previous evidences suggest a link between bone anti-resorptive therapy and vasoprotective/renoprotective effects through mechanisms that remain unexplored. The aim of this study is to assess the renoprotective effect of denosumab and involvement of denosumab-induced reduction in serum Pi in osteoporotic patients. Osteoporotic patients (n = 73) without overt proteinuria in dipstick test results were treated with denosumab (60 mg) every 6 months during the study period (24 months). Estimated glomerular filtration rate based on serum cystatin C (eGFRcys) was used as a filtration marker and tartrate-resistant acid phosphatase-5b (TRACP-5b) as a bone resorption marker. For analysis of non-CKD patients (n = 56), those with eGFRcys <60 mL/min/1.73 m2 were excluded. A single injection of denosumab suppressed serum Pi as well as TRACP-5b during the first 6 months, whereas age-related decline in eGFRcys was significantly reversed, with an increase of 2.75 ± 1.2 mL/min/1.73 m2 after 24 months noted. Multivariate analysis showed that serum Pi reduction following the initial denosumab injection was positively associated with serum TRACP-5b suppression during that same period (ß = 0.241, p = 0.049). In addition, a positive association of serum Pi suppression, but not of corrected calcium or TRACP-5b, with eGFRcys increase after 24 months (ß = 0.321, p = 0.014) was found after adjustments for gender, age, BMI, antihypertensive drug use, albumin, and eGFRcys. The same was observed in osteoporotic cases restricted to non-CKD patients. In conclusion, serum Pi reduction resulting from phosphorus load decrement from bone induced by denosumab is a determinant for eGFRcys increase. Early introduction of bone antiresorptive therapy can retain glomerular filtration in osteoporosis cases, including non-CKD patients. © 2019 American Society for Bone and Mineral Research.

Attenuated Dentin Matrix Protein 1 Enhances Fibroblast Growth Factor 23 in Calvaria in a Primary Hyperparathyroidism Model.

Fibroblast growth factor 23 (FGF23) secretion is facilitated by the PTH, particularly in hyperparathyroidism. The PTH also attenuates dentin matrix protein 1 (DMP1), which is produced by osteocytes to contribute to bone mineralization and suppress FGF23 expression. Nevertheless, it remains unknown whether attenuated DMP1 affects FGF23 expression in hyperparathyroidism. We examined their expression in bone tissue using a mouse model of primary hyperparathyroidism (PHPT). PHPT mice increased serum FGF23 levels, along with a high level of serum PTH. Fgf23 expression increased, and Dmp1 decreased significantly in the calvaria of PHPT mice compared with wild-type mice and primary osteoblasts treated with PTH. In UMR106 mature osteoblasts, PTH increased Fgf23 expression and decreased Dmp1 expression, and stimulation of protein kinase A (PKA) signaling by forskolin also increased Fgf23 expression and decreased Dmp1 expression in a dose-dependent manner, whereas inhibition of PKA signaling with 10-5 M H89 reversed the changes in Fgf23 and Dmp1 expression when cells were stimulated with PTH. Silencing Dmp1 along with PTH treatment led to an additive increase in Fgf23 expression, accompanied by additive phosphorylation of the cAMP-response element-binding protein. These results indicate that persistent and high levels of PTH lead to the continuous activation of PKA signaling in osteoblasts/osteocytes, resulting in an increase in FGF23 and a decrease in DMP1 in bone. Moreover, suppression of DMP1 enhanced FGF23 expression in PHPT, besides having a direct effect on PTH. These mechanisms may describe one of the pathogeneses behind the increase in FGF23 transcription in bone tissue in patients with PHPT.

Effects of Teriparatide and Sequential Minodronate on Lumbar Spine Bone Mineral Density and Microarchitecture in Osteoporosis.

The trabecular bone score (TBS) is a new surrogate for trabecular bone microarchitecture assessment, independent of bone mineral density (BMD), calculated from pixel gray-level variations in the lumbar spine (LS) dual-energy X-ray absorptiometry (DXA) image. Although Teriparatide (TPTD) increased LS-BMD as well as TBS in 2 years, the precise time-course of these parameters was not well known. The aim of this study was to determine the changes in LS-BMD and the TBS in osteoporotic patients treated with TPTD, followed by minodronate (MINO). Primary osteoporotic patients with a low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with TPTD subcutaneously at 20 µg/day for 12-24 months, followed by MINO (orally at 50 mg/once monthly) for 12 months. LS-BMD and the TBS were measured at 0, 3, 6, 12, and 24 months after the initiation of TPTD treatment, and 12 months after the initiation of MINO. The increments of LS-BMD, significant at 6 months, increased until 12 months, whereas the increments of TBS, significant at 3 months (0.035 ± 0.011; p = 0.045 vs. the baseline), stabilized until 12 months. TPTD treatment, followed by 12 months of MINO, maintained both BMD and the TBS. Comparing the increments of the TBS to those of LS-BMD, our results indicate that TPTD treatment improved trabecular microarchitecture faster than mineralization. TPTD treatment, followed by MINO, can maintain both BMD and the TBS.

Teriparatide Therapy Reduces Serum Phosphate and Intima-Media Thickness at the Carotid Wall Artery in Patients with Osteoporosis.

Although cross-sectional and longitudinal studies report a relationship between osteoporosis and cardiovascular disorders (known as the bone-cardiovascular axis), the benefits of osteoporosis treatment on atherosclerosis are largely unclear. Teriparatide is a bone-forming agent that increases urinary phosphate excretion. Because elevated serum phosphate is associated with the development of atherosclerosis, the purpose of our study was to examine the relationship among lumbar spine bone mineral density (LS-BMD), intima-media thickness at the carotid artery (CA-IMT), and phosphate metabolism in response to daily teriparatide therapy. Osteoporotic patients (n = 28) with low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with teriparatide (20 µg/day) for 12 months. Metabolic bone markers, LS-BMD, and CA-IMT were measured over the course of treatment. The LS-BMD significantly increased by 0.046 ± 0.038 g/cm(2) over the 12-month period (P < 0.001). CA-IMT decreased from 0.701 mm (interquartile range: 0.655-0.774 mm) at baseline to 0.525 mm (0.477-0.670 mm) at 12 months (P < 0.05); however, CA-IMT change was not significantly associated with LS-BMD change. Serum phosphate decreased after 1 month of teriparatide administration, and the change in serum phosphate at 1 months was associated with the change in CA-IMT at 12 months (ρ = 0.431, P = 0.025). Teriparatide improved LS-BMD and CA-IMT, suggesting the existence of the bone-cardiovascular axis. The association between serum phosphate and CA-IMT suggests that the teriparatide decreased CA-IMT in part by reducing serum phosphate, a well-known vascular toxin, in addition to the improvement of bone-cardiovascular axis.

Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5 mg daily for 8 weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12 months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N-terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat-treatment group was limited.