Enhanced phagocytic capacity endows chondrogenic progenitor cells with a novel scavenger function within injured cartilage.

OBJECTIVE: Articular cartilage harbors chondrogenic progenitor cells (CPCs), a population that responds chemotactically to cell death. Because this behavior is reminiscent of macrophages, we hypothesized that CPCs have macrophage-like capabilities for scavenging cell and tissue debris through phagocytosis. DESIGN: CPCs, chondrocytes, synoviocytes, and macrophages were cultured with fluorophore-labeled chondrocyte debris for 3, 6, 12, or 24 h. Debris internalization was quantified by confocal microscopy and flow cytometry. Confocal microscopy was also used to test CPCs and chondrocytes for uptake of fluorophore-labeled fibronectin fragments (Fn-fs), a form of extracellular matrix debris. Lysosome activity and mass in CPCs and chondrocytes were measured using fluorescent probes. The relative expression of phagocytosis-related genes and proteins was evaluated by polymerase chain reaction (PCR) and immunoblotting, respectively. Pulse-chase experiments were performed to determine if the debris internalized by CPCs and chondrocytes was cleared, and if clearance was affected by a cathepsin B inhibitor. RESULTS: More macrophages, synoviocytes, and CPCs internalized cell debris than chondrocytes at all time points. While uptake remained flat in chondrocytes at ∼10%, in the other cell types it peaked at more than 60% after 12-24 h. Relative to chondrocytes, CPCs showed significantly higher rates of Fn-fs engulfment, greater lysosome activity and mass, and over-expressed phagocytosis-related genes and proteins. Pulse-chase experiments revealed time- and cathepsin B-dependent clearance of cell debris in CPCs, but not in chondrocytes. CONCLUSIONS: CPCs phagocytized cell and matrix debris much more efficiently than chondrocytes, supporting the hypothesis that they play a macrophage-like role in injured cartilage.

Clinical outcomes of patellar chondral lesions treated with juvenile particulated cartilage allografts.

BACKGROUND: Juvenile particulated cartilage allograft (DeNovo NT®, Zimmer, Warsaw, IN) transplantation is a relatively new technology for the treatment of high-grade cartilage lesions. To date there is limited literature demonstrating its effectiveness and safety. The present study specifically looks at the short-term efficacy of DeNovo NT® allograft for symptomatic high-grade cartilage lesions of the patella. Clinical outcomes and complications are reported. METHODS: Seventeen cases of DeNovo NT® allograft transplantation at our institution were retrospectively reviewed from 2010 to 2013. Thirteen patients had the procedure performed for patellar lesions and are included in the present study. A chart review was performed to record demographic data, surgical technique, and complications. In addition, we analyzed preoperative and postoperative KOOS outcome scores. RESULTS: The mean age was 22.5 years (range, 14-34), with 3 males and 10 females. Mean follow-up was 8.2 months (range, 0.67-32.7). Six of the patients had concomitant anteromedialization of the tibial tubercle. DeNovo NT® allograft transplantation resulted in improvement for each outcome measure used. Overall KOOS score significantly improved from a mean of 58.4±15.7 to 69.2±18.6 (P = 0.04). Improvement in KOOS subscales of pain, ADL, and symptoms all approached but did not reach statistical significance (P values between 0.05 and 0.10). There were no infections or hardware complications. CONCLUSIONS: This series demonstrates that DeNovo NT® allograft transplantation for symptomatic high-grade cartilage lesions of the patella results in pain relief and improved outcomes in the short term. Further studies are needed to better evaluate this new technology. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Single cell sorting identifies progenitor cell population from full thickness bovine articular cartilage.

OBJECTIVE: To date, no approved clinical intervention successfully prevents the progressive degradation of injured articular cartilage that leads to osteoarthritis (OA). Stem/progenitor cell populations within tissues of diarthrodial joint have shown their therapeutic potential in treating OA. However, this potential has not been fully realized due in part to the heterogeneity of these subpopulations. Characterization of clonal populations derived from a single cell may help identify more homogenous stem/progenitor populations within articular cartilage. Moreover, chondrogenic potential of clonal populations from different zones could be further examined to elucidate their differential roles in maintaining articular cartilage homeostasis. METHOD: We combined Fluorescence-activated cell sorting (FACS) and clonogenicity screening to identify stem/progenitor cells cloned from single cells. High-efficiency colony-forming cells (HCCs) were isolated, and evaluated for stem/progenitor cell characteristics. HCCs were also isolated from different zones of articular cartilage. Their function was compared by lineage-specific gene expression, and differentiation potential. RESULTS: A difference in colony-forming efficiency was observed in terms of colony sizes. HCCs were highly clonogenic and multipotent, and overexpressed stem/progenitor cell markers. Also, proliferation and migration associated genes were over-expressed in HCCs. HCCs showed zonal differences with deep HCCs more chondrogenic and osteogenic than superficial HCCs. CONCLUSION: Our approach is a simple yet practical way to identify homogeneous stem/progenitor cell populations with clonal origin. The discovery of progenitor cells demonstrates the intrinsic self-repairing potential of articular cartilage. Differences in differentiation potential may represent the distinct roles of superficial and deep zone stem/progenitor cells in the maintenance of articular cartilage homeostasis.

Mitochondrial electron transport and glycolysis are coupled in articular cartilage.

OBJECTIVE: Although the majority of the adenosine triphosphate (ATP) in chondrocytes is made by glycolysis rather than by oxidative phosphorylation in mitochondria there is evidence to suggest that reactive oxygen species produced by mitochondrial electron transport (ET) help to maintain cellular redox balance in favor of glycolysis. The objective of this study was to test this hypothesis by determining if rotenone, which inhibits ET and blocks oxidant production inhibits glycolytic ATP synthesis. DESIGN: Bovine osteochondral explants were treated with rotenone, an ET inhibitor; or oligomycin an ATP synthase inhibitor; or 2-fluoro-2-deoxy-D-glucose, a glycolysis inhibiter; or peroxide, an exogenous oxidant; or mitoquinone (MitoQ), a mitochondria-targeted anti-oxidant. Cartilage extracts were assayed for ATP, nicotine adenine dinucleotide (NAD+/H), and culture medium was assayed for pyruvate and lactate after 24 h of treatment. Imaging studies were used to measure superoxide production in cartilage. RESULTS: Rotenone and 2-FG caused a significant decline in cartilage ATP (P < 0.001). In contrast, ATP levels were not affected by oligomycin. Peroxide treatment blocked rotenone effects on ATP, while treatment with MitoQ significantly suppressed ATP levels. Rotenone and 2-FG caused a significant decline in pyruvate, but not in lactate production. NADH:NAD+ ratios decreased significantly in both rotenone and 2-FG-treated explants (P < 0.05). Rotenone also significantly reduced superoxide production. CONCLUSIONS: These findings showing a link between glycolysis and ET are consistent with previous reports on the critical need for oxidants to support normal chondrocyte metabolism. They suggest a novel role for mitochondria in cartilage homeostasis that is independent of oxidative phosphorylation.

Biomechanical disc culture system: feasibility study using rat intervertebral discs.

A small-scale biomechanical disc culture system was designed to stimulate intervertebral disc (IVD) 'motion segment' in culture environment with load-controlled compression and combined load (compression+shear). After 7 days of diurnal mechanical loading, cell viability of discs stimulated with static compression load (0.25 MPa) and static combined load (compression (0.25 MPa)+shear (1.5N)) were similar (>90 per cent) to unloaded controls. Mechanically stimulated discs showed decrease in static/dynamic moduli, early stress relaxation, and loss of disc height after 7 days of diurnal loading. Histological data of discs indicated load-induced transformations that were not apparent in controls. The feasibility of studying the mechanobiology of intact IVD as a motion segment was demonstrated. Media conditioning (improve tissue stability in long-term culture) and application of biochemical gene expression assays (differential tissue response to types of mechanical stimulation) are proposed as future improvements. The study suggests that the limitations in studying mechanobiology of IVD pathology in vitro can be overcome and it is possible to understand the physiologically relevant mechanism of IVD pathology.

Mechanical impact induces cartilage degradation via mitogen activated protein kinases.

OBJECTIVE: To determine the activation of Mitogen activated protein (MAP) kinases in and around cartilage subjected to mechanical damage and to determine the effects of their inhibitors on impaction-induced chondrocyte death and cartilage degeneration. DESIGN: The phosphorylation of MAP kinases was examined with confocal microscopy and immunoblotting. The effects of MAP kinase inhibitors on impaction-induced chondrocyte death and proteoglycan (PG) loss were determined with fluorescent microscopy and 1, 9-Dimethyl-Methylene Blue (DMMB) assay. The expression of catabolic genes at mRNA levels was examined with quantitative real-time PCR. RESULTS: Early p38 activation was detected at 20 min and 1h post-impaction. At 24h, enhanced phosphorylation of p38 and extracellular signal-regulated protein kinase (ERK)1/2 was visualized in chondrocytes from in and around impact sites. The phosphorylation of p38 was increased by 3.0-fold in impact sites and 3.3-fold in adjacent cartilage. The phosphorylation of ERK-1 was increased by 5.8-fold in impact zone and 5.4-fold in adjacent cartilage; the phosphorylation of ERK-2 increased by 4.0-fold in impacted zone and 3.6-fold in adjacent cartilage. Furthermore, the blocking of p38 pathway did not inhibit impaction-induced ERK activation. The inhibition of p38 or ERK pathway significantly reduced injury-related chondrocyte death and PG losses. Quantitative Real-time PCR analysis revealed that blunt impaction significantly up-regulated matrix metalloproteinase (MMP)-13, Tumor necrosis factor (TNF)-α, and ADAMTS-5 expression. CONCLUSION: These findings implicate p38 and ERK mitogen activated protein kinases (MAPKs) in the post-injury spread of cartilage degeneration and suggest that the risk of post-traumatic osteoarthritis (PTOA) following joint trauma could be decreased by blocking their activities, which might be involved in up-regulating expressions of MMP-13, ADAMTS-5, and TNF-α.

Evidence for direct projections from the basal nucleus of the amygdala to retrosplenial cortex in the Macaque monkey.

The role of the primate retrosplenial cortex (RSC) in memory processing and spatial navigation has been well established. Recently, processing emotionally salient information has been attributed to the RSC as well. Little anatomical data, however, exist linking the RSC with known emotional processing centers within the brain. The amygdala has been implicated as a substrate for modulating memory for emotionally salient events; yet no study to date has demonstrated that this area has a direct connection in the primate brain. With modern retrograde tracer injections into the RSC and adjacent cortical areas of the monkey (Macaca fascicularis), we demonstrate that there are efferent projections from the basal nucleus of the amygdala to the RSC and area 31. These projections offer anatomical data supporting the hypothesis that the RSC might receive emotionally salient input directly from the amygdala and suggest a role for the RSC as a node within a neural system potentially capable of integrating emotional information for use in memory or other cognitive processes.

Antioxidants block cyclic loading induced chondrocyte death.

Articular cartilage in congruous joints benefits from the moderate stresses and strains associated with normal cyclic loading. However, loading of joints with surface incongruities can lead to local stress and strain elevation at "step-off' sites where cartilage is not fully buttressed b ysurrounding matrix. Excessive stresses and strains predicted to occur at such sites may induce apoptosis, a process thought to promote cartilage degeneration and osteoarthritis (OA) through chondrocyte attrition. We hypothesized that the induction of apoptosis is mediated by oxidants, and that antioxidants can reduce elevated stress-induced chondrocyte attrition. To test this we exposed cylindrical cartilage explants from human articular cartilage to radially unconfined cyclic axial compression (3600 cycles, 1 Hz, 50% duty cycle) using two different physiologic loads (2MPa and 5 MPa). We found that 30% of chondrocytes in the superficial zone died within 24 hours of exposure to loading with 5 MPa axial compression, whereas mortality was limited to less than 15% with 2 MPa axial compression. Similarly, lactate accumulation in the medium was suppressed by compression with 5 MPa, but not 2 MPa. Approximately 80% of cell death induced by 5 MPa compression was blocked by pre-incubation of the explants in a variety of anti-oxidants including vitamin E, n-acetyl cysteine (NAC), and a superoxide dismutase mimetic (SOD). SOD and NAC also prevented the suppression of lactate secretion after 5 MPa compression. These observations support the hypothesis that the harmful effects of abnormal cyclic loading are mediated by oxidants and suggest that treatments to prevent OA may include methods of minimizing oxidative damage to chondrocytes.

Post-traumatic osteoarthritis: the role of stress induced chondrocyte damage.

Post-traumatic osteoarthritis is the form of osteoarthritis (OA) that develops following joint injury. Although its end-stage is indistinguishable from idiopathic OA, many patients with post-traumatic OA are younger than those with idiopathic OA, and they have a well-defined precipitating insult. Clinical and experimental studies suggest that excessive acute impact energy or chronic mechanical overload cause the degeneration of the articular surface responsible for post-traumatic OA. Yet, the mechanisms by which excessive mechanical force causes OA remain unknown. For these reasons it has not been possible to develop effective methods of preventing or decreasing the risk of post-traumatic OA. We hypothesized that mechanical loading that exceeds the tolerance of the articular surface causes chondrocyte damage due to oxidative stress. Our in vitro tests of human articular cartilage samples showed that shear stress causes chondrocyte death and that anti-oxidants decrease the shear stress induced cell death. These observations suggest that specific patterns of loading are particularly damaging to articular surfaces and that improved treatments of joint injuries may include mechanical methods of minimizing shear stresses and biologic methods of minimizing oxidative damage.

Intracortical chondroma: a report of two cases.

Intracortical chondromas are exceedingly rare lesions that have the histopathologic appearance of enchondromas, but are located within cortical bone. Two new cases of intracortical chondroma, one symptomatic and the other found incidentally, are presented and the entity's brief literature reviewed.

Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity.

OBJECTIVE: Although available nonsurgical pharmacotherapies for treatment of osteoarthritis (OA) are considered to be solely symptom-modifying agents, recent advances have been made in the search for agents that may modify disease progression. Intra-articular hyaluronan (HA) therapy is one symptom-modifying approach that has been found to be safe and effective for reducing pain due to OA of the knee. Presented here is a review of the evidence that HAs may also modify the rate of OA disease progression in addition to providing symptomatic efficacy. DESIGN: A review of the literature based on a MEDLINE search through June 2004, using the terms HA, sodium hyaluronate, hyaluronic acid, hylan, hylan G-F 20, OA, disease modification, structure modifying and joint structure. RESULTS: Evidence for disease-modifying activity of HAs stems from 1) the complex biochemical effects of HAs in the synovium and extracellular matrix of the articular cartilage, including interactions between exogenously administered HA and articular cartilage, subchondral bone, matrix proteoglycans, and collagens; 2) the effects of HA administration in animal models of OA, including total or partial meniscectomy and anterior cruciate ligament transectomy; 3) results of clinical trials using one HA, Hyalgan (sodium hyaluronate, molecular weight 500-730 kDa) that evaluated structural outcomes, such as joint-space width, chondrocyte density and vitality, and arthroscopic evaluation of chondropathy. DISCUSSION: Growing preclinical and clinical evidence supports the notion that, in addition to relieving the symptoms of OA, HAs also modify the structure of the diseased joint and the rate of OA disease progression, at least early in the evolution of the disease process.

Osteochondral repair of primate knee femoral and patellar articular surfaces: implications for preventing post-traumatic osteoarthritis.

The risk of post-traumatic osteoarthritis following an intra-articular fracture is determined to large extent by the success or failure of osteochondral repair. To measure the efficacy of osteochondral repair in a primate and determine if osteochondral repair differs in the patella (PA) and the medial femoral condyle (FC) and if passive motion treatment affects osteochondral repair, we created 3.2 mm diameter 4.0 mm deep osteochondral defects of the articular surfaces of the PA and FC in both knees of twelve skeletally mature cynomolgus monkeys. Defects were treated with intermittent passive motion (IPM) or cast-immobilization (CI) for two weeks, followed by six weeks of ad libitum cage activity. We measured restoration of the articular surface, and the volume, composition, type II collagen concentration and in situ material properties of the repair tissue. The osteochondral repair response restored a mean of 56% of the FC and 34% of the PA articular surfaces and filled a mean of 68% of the chondral and 92% of the osseous defect volumes respectively. FC defect repair produced higher concentrations of hyaline cartilage (FC 83% vs. PA 52% in chondral defects and FC 26% vs. PA 14% in osseous defects) and type II collagen (FC 84% vs. PA 71% in chondral defects and FC 37% vs. PA 9% in osseous defects) than PA repair. IPM did not increase the volume of chondral or osseous repair tissue in PA or FC defects. In both PA and FC defects, IPM stimulated slightly greater expression of type II collagen in chondral repair tissue (IPM 81% vs. CI 74%); and, produced a higher concentration of hyaline repair tissue (IPM 62% vs. CI 42%), but IPM produced poorer restoration of PA articular surfaces (IPM 23% vs. CI 45%). Normal articular cartilage was stiffer, and had a larger Poisson's ratio and less permeability than repair cartilage. Overall Cl treated repair tissue was stiffer and less permeable than IPM treated repair tissue. The stiffness, Poisson's ratio and permeability of femoral condyle cast immobilized (FC CI) treated repair tissue most closely approached the normal values. The differences in osteochondral repair between FC and PA articular surfaces suggest that the mechanical environment strongly influences the quality of articular surface repair. Decreasing the risk of post-traumatic osteoarthritis following intra-articular fractures will depend on finding methods of promoting the osteochondral repair response including modifying the intra-articular biological and mechanical environments.

The role of tenascin-C in adaptation of tendons to compressive loading.

Although most tendon regions are subjected primarily to high tensile loads, selected regions, primarily those that directly contact bones that change the direction of the tendon, must withstand high compressive loads as well. Compressed tendon regions differ from regions subjected to primarily tensile loads: they have a fibrocartilaginous structure with spherical cells surrounded by a matrix containing aggrecan and collagen types I and II, in contrast regions not exposed to compression have a fibrous structure with spindle shaped fibroblasts surrounded by a matrix of dense, longitudinally oriented type I collagen fibrils. The spherical shape of cells in fibrocartilagenous regions indicates these cells are more loosely attached to the matrix than their spindle-shaped counterparts in fibrous regions, a feature that may help to minimize cell deformation during tendon compression. We hypothesized that expression of tenascin-C, an anti-adhesive protein, is part of the adaptation of tendon cells to compression that helps establish and maintain fibrocartilaginous regions. To test this hypothesis we compared tenascin-C content and expression in compressed (distal) versus uncompressed (proximal) segments of bovine flexor tendons. Immunohistochemistry and immunoblot analyses showed that tenascin-C content was increased in the distal tendon where it co-distributed with type II collagen and aggrecan. Tendon cells from the distal segments expressed more tenascin-C than did cells from the proximal segments for up to four days in cell culture, indicating that increased tenascin-C expression is a relatively stable feature of the distal cells. These observations support the hypothesis that tenascin-C expression is a cellular adaptation to compression that helps establish and maintain fibrocartilagenous regions of tendons.

Articular cartilage injuries.

The acute and repetitive impact and torsional joint loading that occurs during participation in sports can damage articular surfaces causing pain, joint dysfunction, and effusions. In some instances, this articular surface damage leads to progressive joint degeneration. Three classes of chondral and osteochondral injuries can be identified based on the type of tissue damage and the repair response: (1) damage to the joint surface that does not cause visible mechanical disruption of the articular surface, but does cause chondral damage and may cause subchondral bone injury; (2) mechanical disruption of the articular surface limited to articular cartilage; and (3) mechanical disruption of articular cartilage and subchondral bone. In most instances, joints can repair damage that does not disrupt the articular surface if they are protected from additional injury. Mechanical disruption of articular cartilage stimulates chondrocyte synthetic activity, but it rarely results in repair of the injury. Disruption of subchondral bone stimulates chondral and bony repair, but it rarely restores an articular surface that duplicates the biologic and mechanical properties of normal articular cartilage. In selected patients, surgeons have used operative treatments including penetrating subchondral bone, soft tissue grafts, and cell transplants and osteochondral autografts and allografts to restore articular surfaces after chondral injuries. Experimental studies indicate that use of artificial matrices and growth factors also may promote formation of a new joint surface. However, an operative treatment of an articular surface injury that will benefit patients must not just provide a new joint surface, it must produce better long-term joint function than would be expected if the injury was left untreated or treated by irrigation and debridement alone. Therefore, before selecting a treatment for a patient with an articular cartilage injury, the surgeon should define the type of injury and understand its likely natural history.

Co-localization of insulin-like growth factor binding protein 3 and fibronectin in human articular cartilage.

OBJECTIVE: The anabolic cytokine insulin-like growth factor I (IGF-I) stimulates chondrocyte synthesis of matrix macromolecules and several lines of evidence suggest that it has a major role in maintaining articular cartilage and possibly in cartilage repair. Despite the apparent importance of IGF-I in articular cartilage metabolism and its potential importance in joint diseases, little is known about the regulation of IGF-I activity within the tissue. Insulin-like growth factor binding proteins (IGFBPs) bind IGF-I and can modify its activity. At least three IGFBPs are expressed by chondrocytes: IGFBP-3, -4 and -5. Localization of IGFPBs in the articular cartilage extracellular matrix (ECM) could create reservoirs of IGF-I within the articular cartilage ECM and thereby regulate local IGF-I levels. We hypothesized that ECM molecules bind and concentrate IGFPBs in the pericellular/territorial matrix. DESIGN: Semi-quantitative immunohistological measures of co-localization were used to compare the spatial distribution of IGFBP-3, -4, and -5 with the distributions of three peri-cellularly-enriched matrix molecules fibronectin, tenascin-C, and type VI collagen in osteoarthritic and non-osteoarthritic human articular cartilage. Purified proteins were used in an agarose diffusion assay to compare IGFBP-3 binding to the same three matrix proteins. RESULTS: IGFBP-3 associated with fibronectin in the pericellular/territorial matrix (approximately 40% co-localization) but not with tenascin-C, or type VI collagen (approximately 6% and approximately 15% co-localization respectively, P< 0.05). Neither IGFBP-4, nor IGFBP-5 were associated with any of the three ECM proteins (P< 0.05). In agarose diffusion assays IGFBP-3 interacted with fibronectin and heparan sulfate proteoglycan but not with type VI collagen or tenascin-C. CONCLUSIONS: Direct binding between purified IGFBP-3 and fibronectin and the strong co-localization the two proteins in the cartilage matrix support the hypothesis that IGFPB-3 and fibronectin help regulate local IGF-I levels.

Telomere erosion and senescence in human articular cartilage chondrocytes.

Aging and the degeneration of articular cartilage in osteoarthritis are distinct processes, but a strong association exists between age and the incidence and prevalence of osteoarthritis. We hypothesized that this association is due to in vivo replicative senescence, which causes age-related declines in the ability of chondrocytes to maintain articular cartilage. For this hypothesis to be tested, senescence-associated markers were measured in human articular chondrocytes from donors ranging in age from 1 to 87 years. These measures included in situ staining for senescence-associated beta-galactosidase activity, (3)H-thymidine incorporation assays for mitotic activity, and Southern blots for telomere length determinations. We found that senescence-associated beta-galactosidase activity increased with age, whereas both mitotic activity and mean telomere length declined. These findings indicate that chondrocyte replicative senescence occurs in vivo and support the hypothesis that the association between osteoarthritis and aging is due in part to replicative senescence. The data also imply that transplantation procedures performed to restore damaged articular surfaces could be limited by the inability of older chondrocytes to form new cartilage after transplantation.

Focal osteolysis at the junctions of a modular stainless-steel femoral intramedullary nail.

BACKGROUND: During routine follow-up of patients treated with a three-piece stainless-steel modular femoral nail, osteolysis and periosteal reaction around the modular junctions of some of the nails were noted on radiographs. The purpose of this study was to evaluate the prevalence, etiology, and clinical relevance of these radiographic findings. METHODS: Forty-four femoral fractures or nonunions in forty-two patients were treated with a modular stainless-steel femoral intramedullary nail. Seventeen nails were excluded, leaving twenty-seven intramedullary nails in twenty-seven patients for this study. All patients had had a femoral diaphyseal fracture; nineteen had had an acute fracture and eight, a nonunion. These twenty-seven patients returned for radiographs, a physical examination, assessment of functional outcomes, assessment of thigh pain with a visual analog scale, determination of serum chromium levels, and nail removal if desired. A control group of sixteen patients treated with a one-piece stainless-steel femoral intramedullary nail was evaluated with use of the same outcome measures and was compared with the group treated with the modular femoral nail with regard to prevalence of thigh pain and serum chromium levels. Twelve modular femoral nails were removed according to the study protocol. The modular nail junctions were analyzed for corrosion products, and histopathologic analysis of tissue specimens from the femoral canal was performed. RESULTS: The twenty-seven patients were seen at a mean of twenty-one months after fracture fixation; twenty-six of the twenty-seven fractures healed. Twenty-three femora had at least one of three types of abnormalities-osteolysis, periosteal reaction, or cortical thickening--localized to one or both modular junctions. Eighteen patients had severe reactions, defined as osteolysis of > or =2 mm, cortical thickening of > or =5 mm, and/or a periosteal reaction (group 1). Nine patients had mild or no reactions (group 2). Serum chromium levels in group 1 (mean, 1.27 ng/ mL; range, 0.34 to 3.12 ng/mL) were twice as high as those in group 2 (mean, 0.53 ng/mL; range, 0.12 to 1.26 ng/mL). However, this difference did not reach significance with the numbers available. The differences in serum chromium levels between group 1 and the control group with a one-piece nail (mean, 0.26 ng/mL; range, 0.015 to 1.25 ng/mL) (p<0.01) and a control group without an implant (mean, 0.05 ng/mL; range, 0.015 to 0.25 ng/ mL) (p<0.01) were significant. The level of thigh pain recorded on the visual analog scale was also significantly different between group 1 and the control group with a one-piece implant (p = 0.03). Retrieved modular nails had signs of fretting corrosion as well as stainless-steel corrosion products adherent to the junction where the osteolysis occurred. Histologic and spectrographic analysis revealed two types of corrosion products that were consistent with stainless-steel within the peri-implant tissue and were associated with a foreign-body granulomatous response. CONCLUSIONS: The presence of corrosion products at the taper junctions suggests that particulate debris was a major factor in the etiology of the radiographic findings of osteolysis, periosteal reaction, and cortical thickening. Serum chromium levels were substantially elevated in the patients with a modular femoral nail, and such levels may serve as a marker of fretting corrosion of these devices.

The increasing need for nonoperative treatment of patients with osteoarthritis.

Osteoarthritis affects more patients than almost any other musculoskeletal disorder. The number of patients suffering joint pain and stiffness as a result of this disease will increase rapidly in the next decade. Although operative treatments of patients with osteoarthritis will continue to improve and the number of operative procedures will increase slightly in the next decade, only a small fraction of the patients with osteoarthritis will require operative procedures. The most pressing healthcare need for the majority of patients with osteoarthritis is nonoperative care that helps relieve symptoms and improve function, and in some instances slows progression. In rare instances, the symptoms of osteoarthritis improve spontaneously, but most patients need nonoperative care for decades. Orthopaedists need to improve their ability to provide nonoperative care for patients with osteoarthritis. They should be skilled in the early diagnosis of osteoarthritis and in the use of current common nonoperative treatments including patient education, activity modification, shoe modifications, braces, oral analgesics, oral nonsteroidal antiinflammatory medications, oral dietary supplements, and intraarticular injections. Furthermore, orthopaedists should be prepared to incorporate new nonoperative treatments for patients with osteoarthritis into their practice.

Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the disease characterized by joint pain and loss of joint form and function due to articular cartilage degeneration, is not an inevitable consequence of aging, but a strong association exists between age and increasing evidence of OA. Aging changes in articular cartilage that increase the risk of articular cartilage degeneration include fibrillation of the articular surface, decrease in the size and aggregation of proteoglycan aggrecans, increased collagen cross-linking and loss of tensile strength and stiffness. These alterations are most likely primarily the result of aging changes in chondrocyte function that decrease the ability of the cells to maintain the tissue including decreased synthetic activity, synthesis of smaller less uniform aggrecans and less functional link proteins and decreased responsiveness to anabolic growth factors. Our recent work suggests that the cause of the age-related loss of chondrocyte function may be progressive senescence of articular cartilage chondrocytes marked by a decline in mitotic activity, increased expression of the senescence-associated enzyme beta-galactosidase and erosion of telomere length. New efforts to prevent the development or progression of OA might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.