Direct cell–cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo

Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial–temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell–cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell–cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell–cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide

Introduction: The pharmacokinetic profile of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment. Methods: We treated 17 female New Zealand white rabbits aged 6 months for 1 month with teriparatide [human PTH(1-34)] as follows. (i) Vehicle-treated Control (n = 4); (ii) 20 μg/kg daily (n = 3); (iii) 40 μg/kg daily (n = 3); (iv) 140 μg/kg weekly (n = 3); (v) 280 μg/kg weekly (n = 4). Proximal femurs were imaged ex vivo using micro-CT (Scanco Viva CT-40) at 15 μm voxel size. Areas, pore size, and porosity were analyzed on the total, compact cortex (CC), and transitional zones in a 10 mm length region of interest (ROI) starting at the midshaft using StrAx1.0. Results: Compared to controls, the 20 μg/kg daily was associated with 3.0% higher porosity in the transitional zone (p = 0.09) while the 40 μg/kg daily was associated with a higher porosity in the cortex (8.7%; p = 0.04) and in the transitional zone (5.7%; p = 0.007). The daily regimens were also associated with a greater proportion of porosity due to pores > 15 μm2; particularly in the transitional zone where 20 and 40 μg/kg daily increased porosity 2 fold (p = 0.06) and 5 fold (p = 0.04) relative controls respectively. The 140 and 280 μg/kg weekly were not associated with an increase in porosity. There was no difference in total, compact or transitional zone cross sectional areas between the groups. Conclusion: Effects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation

Comparative Study of S2-Alar-Iliac Screw Trajectories between Males and Females Using Three-Dimensional Computed Tomography Analysis: The True Lateral Angulation of the S2-Alar-Iliac Screw in the Axial Plane

The S2 alar-iliac screw (S2AIS) is commonly used for long spinal fusion as a rigid distal foundation in spinal deformity surgeries, and it is also used in percutaneous sacropelvic fixation for providing an in-line connection to the proximal spinal constructs without using offset connectors. Although the pelvic shape is different between males and females, reports on S2AIS trajectories according to gender have been scarce in the literature. In this paper, S2AIS trajectories are compared between males and females using pelvic three-dimensional computed tomography (3D-CT) in a normal Japanese population. After resetting the caudal angulation in CT-imaging plane manipulation, the angulation of S2AIS was more lateral in the axial plane and more horizontal in the coronal plane in females. Mean distances from the midline to starting points of S2AIS tended to be shorter in females, whereas mean distances from the midline to the posterior superior iliac spine was significantly longer in females. We also found that there were positive correlations between the patients’ height and the maximal lengths of S2AISs, and the patients’ height and minimal areas of S2AIS pathways. Our results are useful not only for conventional open spinal surgery, but also for minimally invasive spine surgery

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit

<div><p>Teriparatide [human parathyroid hormone (1–34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment.</p></div

Magnified images of the endosteum region of the tibiae shown in Fig 4.

<p>Zoom-in views of the medial endosteum region from large views (the white boxed area in each panel) shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175329#pone.0175329.g004" target="_blank">Fig 4</a>. The yellow arrowheads indicate the fibroblastic cell-enriched tissue layer covering the bone surface. These tissue layers in D20 and D40 exhibit the typical appearance of bone marrow fibrosis. Scale bars, 200 μm.</p