Effects of proteasome inhibitors on cytokines, metalloproteinases and their inhibitors and collagen type-I expression in periprosthetic tissues and fibroblasts from loose arthroplasty endoprostheses.

Objective: Aseptic loosening is a major problem in total joint replacement. Implant wear debris provokes a foreign body host response and activates cells to produce a variety of mediators and ROS, leading to periprosthetic osteolysis. Elevated ROS levels can harm proteasome function. Proteasome inhibitors have been reported to alter the secretory profile of cells involved in inflammation and also to induce ROS production. In this work, we aimed to document the effects of proteasome inhibitors MG-132 and Epoxomicin, on the production of factors involved in aseptic loosening, in periprosthetic tissues and fibroblasts, and investigate the role of proteasome impairment in periprosthetic osteolysis. Materials and methods: IL-6 levels in tissue cultures were determined by sandwich ELISA. MMP-1, -3, -13, -14 and TIMP-1 levels in tissue or cell cultures were determined by indirect ELISA. Results for MMP-1 and TIMP-1 in tissue cultures were confirmed by Western blotting. MMP-2 and MMP-9 levels were determined by gelatin zymography. Gene expression of IL-6, MMP-1,-3,-14, TIMP-1 and collagen type-I was determined by RT-PCR. Results: Results show that proteasome inhibition induces the expression of ΜΜΡ-1, -2, -3, -9 and suppresses that of IL-6, MMP-14, -13, TIMP-1 and collagen type I, enhancing the collagenolytic and gelatinolytic activity already present in periprosthetic tissues, as documented in various studies. Conclusions: These findings suggest that proteasome impairment could be a contributing factor to aseptic loosening. Protection and enhancement of proteasome efficacy could thus be considered as an alternative strategy toward disease treatment.

Western-type diet differentially modulates osteoblast, osteoclast, and lipoblast differentiation and activation in a background of APOE deficiency.

During the past few years, considerable evidence has uncovered a strong relationship between fat and bone metabolism. Consequently, alterations in plasma lipid metabolic pathways strongly affect bone mass and quality. We recently showed that the deficiency of apolipoprotein A-1 (APOA1), a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, results in reduced bone mass in C57BL/6 mice. It is documented that apolipoprotein E (APOE), a lipoprotein know for its atheroprotective functions and de novo biogenesis of HDL-C, is associated with the accumulation of fat in the liver and other organs and regulates bone mass in mice. We further studied the mechanism of APOE in bone metabolism using well-characterized APOE knockout mice. We found that bone mass was remarkably reduced in APOE deficient mice fed Western-type diet (WTD) compared to wild type counterparts. Static (microCT-based) and dynamic histomorphometry showed that the reduced bone mass in APOΕ-/- mice is attributed to both decreased osteoblastic bone synthesis and elevated osteoclastic bone resorption. Interestingly, histologic analysis of femoral sections revealed a significant reduction in the number of bone marrow lipoblasts in APOΕ-/- compared to wild type mice under WTD. Analyses of whole bone marrow cells obtained from femora of both animal groups showed that APOE null mice had significantly reduced levels of the osteoblastic (RUNX2 and Osterix) and lipoblastic (PPARγ and CEBPα) cardinal regulators. Additionally, the modulators of bone remodeling RANK, RANKL, and cathepsin K were greatly increased, while OPG and the OPG/RANKL ratio were remarkably decreased in APOΕ-/- mice fed WTD, compared to their wild-type counterparts. These findings suggest that APOE deficiency challenged with WTD reduces osteoblastic and lipoblastic differentiation and activity, whereas it enhances osteoclastic function, ultimately resulting in reduced bone mass, in mice.

Extracellular matrix degradation and tissue remodeling in periprosthetic loosening and osteolysis: focus on matrix metalloproteinases, their endogenous tissue inhibitors, and the proteasome.

The leading complication of total joint replacement is periprosthetic osteolysis, which often results in aseptic loosening of the implant, leading to revision surgery. Extracellular matrix degradation and connective tissue remodeling around implants have been considered as major biological events in the periprosthetic loosening. Critical mediators of wear particle-induced inflammatory osteolysis released by periprosthetic synovial cells (mainly macrophages) are inflammatory cytokines, chemokines, and proteolytic enzymes, mainly matrix metalloproteinases (MMPs). Numerous studies reveal a strong interdependence of MMP expression and activity with the molecular mechanisms that control the composition and turnover of periprosthetic matrices. MMPs can either actively modulate or be modulated by the molecular mechanisms that determine the debris-induced remodeling of the periprosthetic microenvironment. In the present study, the molecular mechanisms that control the composition, turnover, and activity of matrix macromolecules within the periprosthetic microenvironment exposed to wear debris are summarized and presented. Special emphasis is given to MMPs and their endogenous tissue inhibitors (TIMPs), as well as to the proteasome pathway, which appears to be an elegant molecular regulator of specific matrix macromolecules (including specific MMPs and TIMPs). Furthermore, strong rationale for potential clinical applications of the described molecular mechanisms to the treatment of periprosthetic loosening and osteolysis is provided.

Intramedullary nailing for the treatment of aseptic femoral shaft non-unions after plating failure: effectiveness and timing.

This retrospective, multicentre study aimed to evaluate reamed intramedullary nailing (IMN) for the treatment of 30 cases of aseptic femoral shaft non-union after plating failure. Following nailing, 29 non-unions had healed by a mean 7.93 months. In one case a hypertrophic non-union required renailing after 8 months, using a nail of greater diameter, and united within five further months. Healing times were not related to whether the fracture was open or closed, the type non-union or the type of fracture. The delay from the initial plating to intramedullary nailing had a statistically significant effect on healing time and final outcome. This treatment is cost effective and should be implemented as soon as the non-union is diagnosed.

Sciatica due to extrapelvic heterotopic ossification: a case report.

INTRODUCTION: Sciatica is a common problem, usually caused by disc herniation or spinal stenosis. Low back pain is also present in most cases. When sciatica is the unique clinical finding, especially in young patients, extraspinal pathology should be investigated. CASE PRESENTATION: We describe a rare case of sciatica in a 32-year-old man, which was developed as a complication of post-traumatic pelvic heterotopic ossification. During the operation, the sciatic nerve was found to be bluish, distorted and compressed in an hourglass fashion around a heterotopic bone mass. The heterotopic bone tissue, 4 cm in diameter, was removed and the patient had fully recovered 3 months after the operation. CONCLUSION: In cases of sciatica without back pain, the possibility of direct pressure of the sciatic nerve from cysts, tumours or bone, as in the present case, should be considered.

Double-loop suture repair for acute acromioclavicular joint disruption.

BACKGROUND: Although it has been established that surgical treatment for acromioclavicular joint disruption (types IV-VI and type III in overhead throwing athletes and heavy laborers) is preferred, the literature is inconclusive about the best type of surgery. PURPOSE: With the goal of avoiding the potential complications of hardware use, the authors present a coracoclavicular functional stabilization technique with the intention to restore the anteroposterior and superior displacement of the clavicle. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 1999 to 2003, 38 patients with an acute, complete acromioclavicular joint separation (34 men, 4 women; mean age, 33.5 years) underwent surgical reconstruction with the described coracoclavicular loop stabilization technique. With this technique, the superior and anteroposterior displacement of the clavicle can be easily controlled using 2 pairs of Ethibond No. 5 nonabsorbable sutures-one passed in front and the other behind the clavicle, through a central drill hole, 2 cm from its lateral end, directly above the base of the coracoid process (at the corresponded attachment of coracoclavicular ligaments). Passive shoulder motion was encouraged by the second postoperative day. RESULTS: Thirty-four patients were available for the last clinical and radiologic evaluation. At a mean follow-up of 33.2 months (range, 18-59 months), the mean Constant-Murley score was 93.5 points (range, 73-100 points), and 2 cases with slight loss of reduction (less than half of the width of the clavicle) were detected. Complications included 1 case with superficial infection and 1 patient (basketball player) with persistent tenderness in the acromioclavicular joint without signs of secondary arthritis. The incidence of periarticular ossification was 17.6% and did not affect the final outcome. Secondary degenerative changes were not detected. CONCLUSION: Considering the nearly anatomical reconstruction, the avoidance of hardware complications, and the low rate of recurrence, this technique may be an attractive alternative to the management of acute acromioclavicular joint separations.