Seppo Santavirta

Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis

OBJECTIVE To define the pattern of mRNA expression of all human matrix metalloproteinases (MMPs) described to date in rheumatoid arthritis (RA) and traumatic synovial membrane, in order to differentiate between a physiological tissue remodelling pattern and that associated with inflammatory tissue destruction. METHODS Analysis of SwissProt protein and EMBL/GenBank nucleotide sequence banks, protein sequence alignment, reverse transcriptase-polymerase chain reaction and nucleotide sequencing were used. RESULTS MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-11 (stromelysin-3) and MMP-19 were constitutively expressed. MMP-1 (fibroblast type collagenase), MMP-9 (gelatinase B) and MMP-14 (MT1-MMP) were expressed in all RA, but only in 55–80% of trauma samples. MMP-13 (collagenase-3) and MMP-15 (MT2-MMP) were expressed exclusively in RA (80–90% of the samples). MMP-20 (enamelysin) was absent and MMP-8 (collagenase-2) was rarely found in RA or trauma. All other MMPs (-7, -10, -12, -16, -17) had an intermediate pattern of expression. CONCLUSIONS Some MMPs without interstitial collagenase activity seem to have a constitutive pattern of expression and probably participate in physiological synovial tissue remodelling. Some MMPs are exclusively associated to RA synovitis, for example, MMP-13, which preferentially degrades type II collagen and aggrecan, and MMP-15, which activates proMMP-2 and proMMP-13 and is involved in tumour necrosis factor α processing. This clear cut rheumatoid/inflammatory MMP profile, more complex than has been previously appreciated, may facilitate inflammatory tissue destruction in RA.

Aggressive granulomatous lesions associated with hip arthroplasty. Immunopathological studies.

The local immunopathological response was analyzed in six patients who had a revision of a total hip prosthesis because of an aggressive granulomatous lesion and in six patients who had a revision because of common loosening of the prosthetic stem. All twelve patients had had a total replacement arthroplasty for primary osteoarthrosis. All of the prostheses had been cemented. The aggressive granulomas consisted of well organized connective tissue containing histiocytic-monocytic and fibroblastic reactive zones. The granulomas were highly vascularized, and villous structures were observed at many sites. In contrast, the areas around the loose cemented stems were characterized by dense connective tissue. Immunohistological evaluation revealed that most of the cells in the aggressive granulomatous tissue were multinucleated giant cells and C3bi-receptor and nonspecific esterase-positive monocyte-macrophages. This cytological finding suggests a foreign-body-type reaction, compatible with the rapidly progressive lytic nature of the lesion that was shown radiographically. There was a clear-cut difference between aggressive granulomatosis and the more common lesion accompanying prosthetic loosening--namely, the relative lack of activated fibroblasts in granulomatosis. We suggest that granulomatosis involves an uncoupling of the normal sequence of monocyte-macrophage-mediated clearance of foreign material and tissue debris that is normally followed by fibroblast-mediated synthesis and remodeling of the extracellular matrix. We also suggest that aggressive granulomatosis in association with a cemented hip prosthesis is a distinct entity, not only clinically and radiographically, but also histopathologically.

Aggressive granulomatous lesions in cementless total hip arthroplasty

We describe six patients with aggressive granulomatous lesions around cementless total hip prostheses. Two patients previously had a cemented prosthesis in the same hip. The Lord prosthesis was used in five patients, the PCA in one. Both prostheses were made of chrome-cobalt alloy. Pain on weight-bearing occurred on average 3.2 years after the cementless arthroplasty, and at that time radiography revealed aggressive granulomatosis around the proximal femoral stem and the acetabular component in five of the patients; one had a large solitary granuloma in the proximal femur. Revision was performed on average 4.8 years after the cementless arthroplasty. At that time all granulomas had grown large in size; while waiting for revision operation, two femoral stem components fractured. All the granulomas showed a uniform histopathology, which included histiocytosis; the cause for these lesions was thought to be plastic debris from the acetabular socket.

Failure of reduction with an external fixator in the management of pelvic ring injuries: LONG-TERM EVALUATION OF 110 PATIENTS

We reviewed 110 patients with an unstable fracture of the pelvic ring who had been treated with a trapezoidal external fixator after a mean follow-up of 4.1 years. There were eight open-book (type B1, B3-1) injuries, 62 lateral compression (type B2, B3-2) and 40 rotationally and vertically unstable (type C1-C3) injuries. The rate of complications was high with loss of reduction in 57%, malunion in 58%, nonunion in 5%, infection at the pin site in 24%, loosening of the pins in 2%, injury to the lateral femoral cutaneous nerve in 2%, and pressure sores in 3%. The external fixator failed to give and maintain a proper reduction in six of the eight open-book injuries, in 20 of the 62 lateral compression injuries, and in 38 of the 40 type-C injuries. Poor functional results were usually associated with failure of reduction and an unsatisfactory radiological appearance. In type-C injuries more than 10 mm of residual vertical displacement of the injury to the posterior pelvic ring was significantly related to poor outcome. In 14 patients in this unsatisfactory group poor functional results were also affected by associated nerve injuries. In lateral compression injuries the degree of displacement of fractures of the pubic rami caused by internal rotation of the hemipelvis was an important prognostic factor. External fixation may be useful in the acute phase of resuscitation but it is of limited value in the definitive treatment of an unstable type-C injury and in type-B open-book injuries. It is usually unnecessary in minimally displaced lateral compression injuries.

Immune response to polyglycolic acid implants

Cytological analysis of material aspirated from the effusion which occasionally develops around a polyglycolic acid (PGA) osteosynthesis implant showed a predominance of inflammatory monocytes and in particular lymphocytes. In order to discover whether PGA implants are immunologically inert, density gradient-isolated peripheral blood mononuclear cells were cultured in 0.2 ml of 10% delta FCS-RPMI 1640 culture medium supplemented with 10 mg PGA. Phytohaemagglutinin (PHA) lectin, a purified protein derivate of tuberculin (PPD) antigen and culture medium alone were used as positive and negative controls. We studied lymphocyte activation kinetics on days 0, 1, 3 and 5. Major histocompatibility complex locus II antigen (MHC locus II antigen) and interleukin-2 receptor (IL-2R) expression were analysed using the avidin-biotin-peroxidase complex (ABC) method and lymphocyte DNA synthesis by using 3H-thymidine incorporation and beta-scintillation counting. Especially on culture days 0 and 1, lymphocytes and monocytes were seen by light microscopy to be attached to PGA particles. However, our results show no PGA-induced lymphocyte DNA synthesis, but PGA-induced MHC locus II antigen and IL-2R activation marker expression was seen, greater than in negative controls, but less than that seen in PPD antigen driven lymphocyte response. This suggests that PGA is an immunologically inert implant material, but it does seem to induce inflammatory mononuclear cell migration and adhesion, leading to a slight non-specific lymphocyte activation. This activation is lower than that seen in mitogen and antigen-driven lymphocyte responses.

Immunopathological response to loose cementless acetabular components

The membranes surrounding seven loose cementless acetabular implants were shown to contain polyethylene particles, birefringent in polarised light. Three of these implants were made of titanium alloy and the membranes around these contained titanium particles as well. There was no metallosis around the four implants made of chromium-cobalt-steel alloy. Both titanium and polyethylene particles caused migration, adherence and phagocytosis of CD11b-positive, peroxidase-negative macrophages. There were no histological signs of activation of the specific immune response; neither interleukin-2 receptor-positive activated T cells nor PCA-1 plasmablasts/plasma cells were present in the tissues. In cases of simple loosening, resident mesenchymal fibroblast-like cells were active. In aggressive granulomatosis, there were many macrophages and multinucleated giant cells but little fibroblast reaction. The clinical relevance of the findings is that the use of cementless prostheses is not a guarantee against adverse tissue reactions.

Operative and Nonoperative Treatments of Medial Collateral Ligament Rupture With Early Anterior Cruciate Ligament Reconstruction A Prospective Randomized Study

Background The apparent consensus is that solitary medial collateral ligament rupture can be treated nonoperatively, but treatment of severe combined ruptures of the medial collateral ligament and anterior cruciate ligament remains controversial. Hypotheses Nonoperative and early operative treatments of grade III medial collateral ligament rupture lead to similar results when the anterior cruciate ligament is reconstructed in the early phase. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods Forty-seven consecutive patients with combined anterior cruciate ligament and grade III medial collateral ligament injuries were randomized into 2 groups. The medial collateral ligament injury was treated operatively in group 1 (n = 23) and nonoperatively in group 2 (n = 24). In both groups, the anterior cruciate ligament injury was treated with early reconstruction, using bone-patellar tendon-bone graft and interference screw. Two years postoperatively, knee stability was measured with a KT-1000 arthrometer and Telos valgus radiography and knee extension strength with a Biodex dynamometer and a 1-legged hop test. An International Knee Documentation Committee evaluation form and Lysholm score were completed. Results All 47 patients were available for clinical evaluation for a mean of 27 months (range, 20-37 months) after surgery. There were no statistically significant differences between the 2 groups with respect to subjective function of the knee, postoperative stability, range of motion, muscle power, return to activities, Lysholm score, and overall International Knee Documentation Committee evaluation. The subjective outcome and Lysholm score were good and anteroposterior knee stability excellent in both groups. Conclusion Nonoperative and operative treatments of medial collateral ligament injuries lead to equally good results. Medial collateral ligament ruptures need not be treated operatively when the anterior cruciate ligament is reconstructed in the early phase.

Neuroimmunohistochemical Analysis of Peridiscal Nociceptive Neural Elements

Twenty-three perioperative tissue samples from lumbar disc operations on 11 patients were studied Immunohistochemically using the sensitive avidin-biotin-peroxidase complex (ABC) method and specific heterologous antisera for the presence of neurofilament-positive neural elements containing nociceptive neuropeptides substance P (SP) and/or calcitonin gene-related peptide (CGRP). Histologically, neural elements were especially abundant in the posterior longitudinal ligament, there being also a few demonstrable nerves in the peripheral anulus fibrosus. These nerves often showed a co-localization of cytoskeletal neurofilaments together with SP and/or CGRP immunoreactivity. It is suggested that pressure and chemical irritation of nociceptive nerves dependent on degenerated discs excite sensory neural elements, especially in the posterior longitudinal ligament and possibly also in the peripheral parts of the anulus fibrosus, while the disc itself, at least if not penetrated by vascular granular tissue, is painless and neuroanatomically lacks a structural basis for pain perception.

Imbalance of RANKL/RANK/OPG system in interface tissue in loosening of total hip replacement

In the differentiation of osteoclasts the differentiation factor (RANKL) interacts with the receptor activator of NF-kappaB (RANK) in a direct cell-to-cell contact between osteoblast and (pre)osteoclast. This is inhibited by soluble osteoprotegerin (OPG). The mRNA levels of both RANKL (p < 0.01) and RANK (p < 0.05) were high in peri-implant tissue and RANKL+ and RANK+ cells were found in such tissue. Double labelling also disclosed soluble RANKL bound to RANK+ cells. We were unable to stimulate fibroblasts to express RANKL in vitro, but monocyte activation with LPS gave a fivefold increase in RANK mRNA levels. In contrast to RANKL and RANK expression in peri-implant tissue, expression of OPG was restricted to vascular endothelium. Endothelial cell OPG mRNA levels were regulated by TNF-alpha and VEGF, but not by hypoxia. It is concluded that activated cells in the interface tissue overproduce both RANKL and RANK and they can interact without interference by OPG.

The Results of Operative Resection of the Lateral End of the Clavicle

Seventy-three patients had operative resection of the lateral end of the clavicle for the treatment of a painful condition of the acromioclavicular joint. Thirty-two of the patients had had a traumatic separation of the acromioclavicular joint, eight had had a fracture of the lateral end of the clavicle, and thirty-three had primary acromioclavicular osteoarthrosis. An average of sixteen millimeters (range, five to thirty-seven millimeters) was resected; the amount was similar in each of the three groups. The patients were evaluated an average of nine years (range, four to sixteen years) after the operation. The result was considered good in twenty-one patients, satisfactory in twenty-nine, and poor in twenty-three. A poor result was more common in the patients who had had a fracture of the lateral end of the clavicle (p < 0.01). Forty-six patients reported pain with exertion, and thirteen noted pain at rest. Eighteen patients had a decrease in the strength of the involved upper extremity, and sixteen had some limitation of the mobility of the shoulder. Elevation of the lateral end of the remaining part of the clavicle as compared with the scapula was noted in eighteen patients and was more likely to be associated with pain (p < 0.05). The extent of the resection was significantly associated with pain; patients who had had a smaller amount of resection (ten millimeters or less) had less pain than those who had had a larger amount (p < 0.03). A good result was more common in the patients in whom less than ten millimeters had been resected and who had had a previous traumatic separation of the acromioclavicular joint or had primary acromioclavicular osteoarthrosis. We recommend that resection of the lateral end of the clavicle be considered with caution for patients who have severe post-traumatic or degenerative osteoarthrosis of the acromioclavicular joint. If resection is performed, it should not exceed ten millimeters.