Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a mutation of lamin A, which contributes to nuclear architecture and the spatial organization of chromatin in the nucleus. The expression of a lamin A mutant, named progerin, leads to functional and structural disruption of nuclear organization. Since progerin lacks a part of the actin-binding site of lamin A, we hypothesized that nuclear actin dynamics and function are altered in HGPS cells. Nuclear F-actin is required for the organization of nuclear shape, transcriptional regulation, DNA damage repair, and activation of Wnt/ß-catenin signaling. Here we show that the expression of progerin decreases nuclear F-actin and impairs F-actin-regulated transcription. When nuclear F-actin levels are increased by overexpression of nuclear-targeted actin or by using jasplakinolide, a compound that stabilizes F-actin, the irregularity of nuclear shape and defects in gene expression can be reversed. These observations provide evidence for a novel relationship between nuclear actin and the etiology of HGPS.

Assessment of thermal damage in total knee arthroplasty using an osteocyte injury model.

Polymethylmethacrylate bone cement has been widely used for the anchorage of artificial implants in various orthopedic surgeries. Although it is one of the most successful biomaterials in use, excess heat generation intrinsically causes thermal damage to bone cells adjacent to the bone cement. To estimate a risk of thermal injury, a response of bone cells to cement polymerization must be elucidated because of the occurrence of thermal damage. Thermal damage is affected not only by maximal temperature but also by exposure time, temperature history, and cell type. This study aimed at quantifying the thermal tolerance of bone cells for the development of a thermal injury model, and applying this model for the estimation of thermal damage during cement polymerization in total knee arthroplasty. Osteocytes, osteoblasts, and fibroblasts were respectively subjected to steady supraphysiological temperatures ranging from 45 to 50°C. Survival curves of each cell and temperatures were used to formulate the Arrhenius model. A three-dimensional heat conduction analysis for total knee arthroplasty was conducted using the finite element model based on serial CT images of human knee. A maximal temperature rise of 50°C was observed at the interface between the 3-mm thick cement and the tissue immediately beneath the tibial tray of the prosthesis. The probability of thermal damage to the osteocyte, which was calculated using the Arrhenius model, was negligible at a distance of at least 1 mm away from the cement-bone interface. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2799-2807, 2017.