Impaired proteoglycan glycosylation, elevated TGF-ß signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica.

Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-ß in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

Arthroscopic patellar release allows timely return to performance in professional and amateur athletes with chronic patellar tendinopathy.

PURPOSE: Return to sports rates in amateur and professional athletes with chronic patellar tendinopathy following arthroscopic patellar release are unpredictable. The present study aims to analyse the effectiveness of arthroscopic patellar release in professional compared to amateur athletes. METHODS: A total of 34 amateur and 20 professional athletes with chronic patellar tendinopathy, refractory to conservative treatment, were studied prospectively and underwent arthroscopic tendon release at the inferior patellar pole. Impact of grouped sports on clinical and functional outcome, subjective patient satisfaction and return to sports rates were assessed. Additionally, preoperative MRI-scans of the knee were evaluated and correlated with clinical outcome. RESULTS: In 40 patients (74.1%) arthroscopic patellar release resulted in complete recovery and return to preinjury exercise levels. Full return to sports was achieved after a median of 3.0 (range 0.5-12.0) months. Functional outcome measures VISA-P (Victorian Institute of sport assessment for patella) and modified Blazina scores improved significantly from pre- to postoperatively (VISA-P: 48.8 vs. 94.0 pts., respectively, p < 0.0001; Blazina: 4.47 vs. 0.5, respectively, p < 0.0001). CONCLUSION: As rapid recovery and timely return to sports are crucial for professional athletes, arthroscopic patellar release should be considered after failed conservative treatment. LEVEL OF EVIDENCE: IV.

Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I.

Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.

Arthroscopic patellar release for treatment of chronic symptomatic patellar tendinopathy: long-term outcome and influential factors in an athletic population.

BACKGROUND: Arthroscopic patellar release (APR) is utilized for minimally invasive surgical treatment of patellar tendinopathy. Evidence regarding long-term success following the procedure is limited. Also, the influence of age and preoperative performance level, are incompletely understood. The aim of this study was to investigate whether APR translates into sustained pain relief over a long-term follow-up in athletes undergoing APR. Furthermore, we analyzed if age influences clinical and functional outcome measures in APR. METHODS: Between 1998 and 2010, 30 competitive and recreational athletes were treated with APR due to chronic refractory patellar tendinopathy. All data were analyzed retrospectively. Demographic data, such as age or level of performance prior to injury were extracted. Clinical as well as functional outcome measures (Swedish Victorian Institute of sport assessment for patella (VISA-P), the modified Blazina score, pain level following exercise, return to sports, and subjective knee function were assessed pre- and postoperatively. RESULTS: In total, 30 athletes were included in this study. At follow-up (8.8 ± 2.82 years), clinical and functional outcome measures such as the mean Blazina score, VISA-P, VAS, and subjective knee function revealed significant improvement compared to before surgery (P < 0.001). The mean time required for return to sports was 4.03 ± 3.18 months. After stratification by age, patients younger than 30 years of age yielded superior outcome in the mean Blazina score and pain level when compared to patients ≥30 years (P = 0.0448). At 8 years of follow-up, patients yielded equivalent clinical and functional outcome scores compared to our previous investigation after four years following APR. CONCLUSION: In summary, APR can be regarded a successful, minimally invasive, and sustained surgical technique for the treatment of patella tendinopathy in athletes. Younger age at surgery may be associated with improved clinical and functional outcome following APR.

Prospective Clinical Trial for Septic Arthritis: Cartilage Degradation and Inflammation Are Associated with Upregulation of Cartilage Metabolites.

Background. Intra-articular infections can rapidly lead to osteoarthritic degradation. The aim of this clinical biomarker analysis was to investigate the influence of inflammation on cartilage destruction and metabolism. Methods. Patients with acute joint infections were enrolled in a prospective clinical trial and the cytokine composition of effusions (n = 76) was analyzed. Characteristics of epidemiology and disease severity were correlated with levels of cytokines with known roles in cartilage turnover and degradation. Results. Higher synovial IL-1ß concentrations were associated with clinical parameters indicating a higher disease severity (p < 0.03) excluding the incidence of sepsis. Additionally, intra-articular IL-1ß levels correlated with inflammatory serum parameters as leucocyte counts (LC) and C-reactive protein concentrations (p < 0.05) but not with age or comorbidity. Both higher LC and synovial IL-1ß levels were associated with increased intra-articular collagen type II cleavage products (C2C) indicating cartilage degradation. Joints with preinfectious lesions had higher C2C levels. Intra-articular inflammation led to increased concentrations of typical cartilage metabolites as bFGF, BMP-2, and BMP-7. Infections with Staphylococcus species induced higher IL-1ß expression but less cartilage destruction than other bacteria. Conclusion. Articular infections have bacteria-specific implications on cartilage metabolism. Collagen type II cleavage products reliably mark destruction, which is associated with upregulation of typical cartilage turnover cytokines. This trial is registered with DRKS00003536, MISSinG.

Posterior root tears of the lateral meniscus.

PURPOSE: To summarize and discuss the current knowledge on posterior lateral meniscus root tears. METHODS: A comprehensive review of the MEDLINE database was carried out to identify relevant articles using different keywords (e.g. "meniscus root", "root tear", "meniscus avulsion", "radial tear" and "lateral meniscus"). The reference lists of the reviewed articles were searched for additional relevant articles. RESULTS: Posterior lateral meniscus root tears are found in 7-12% of patients with a tear of the anterior cruciate ligament (ACL). Biomechanical studies have found an increase in lateral compartment contact pressure of approximately 50% after creation of a posterior lateral meniscus root tear. There is some evidence that the biomechanical consequences of these injuries are significantly influenced by the presence and integrity of the meniscofemoral ligaments. Clinical studies have found encouraging results after repair of posterior lateral meniscus root tears. Whether root repair can prevent the development of osteoarthritis is currently unknown. CONCLUSION: A posterior lateral meniscus root tear is a clinical relevant but most likely underrecognized concomitant injury in patients with a tear of the ACL. This article may support clinicians in diagnosing and treating this unique type of meniscus tear. LEVEL OF EVIDENCE: V.

Simultaneous avulsion fracture of the posterior medial and posterior lateral meniscus root: a case report and review of the literature.

Injuries of the meniscus roots are increasingly recognized as a serious knee joint pathology. An avulsion fracture of the meniscus root is a rare variant of this injury pattern. In this article, a case of a traumatic simultaneous avulsion fracture of both the posterior medial and posterior lateral meniscus root associated with a tear of the anterior cruciate ligament is presented. Both avulsion fractures were treated by indirect arthroscopic transtibial pullout fixation of the bony fragment. Based on the findings of our literature review, root avulsion fractures seem to be more common in young male patients after an acute trauma to the knee joint.

Correlation of synovial cytokine expression with quality of cells used for autologous chondrocyte implantation in human knees.

The cell quality plays a decisive role in autologous chondrocyte implantation (ACI). Aim of the study was the analysis of in vivo interactions between synovial concentrations of cytokines and cell quality used for ACI. Knee lavage fluids of patients undergoing an ACI were examined for total protein content (TPC) and by ELISA for levels of basic fibroblast growth factor (bFGF), insulin-like growth factor 1, bone morphogenetic proteins 2 and 7 (BMP-2 and BMP-7). Cell quality following amplification for ACI was determined by surface expression of CD44, aggrecan, collagen type II and evaluation of cell characteristics. Data of 17 patients were supplemented by epidemiological parameters and clinical scores (IKDC, Lysholm, pain strength, subjective knee function). CD44 expression was positively associated with TPC and bFGF, and negatively linked to BMP-2 levels (p < 0.01). In contrast, expression of collagen type II did not show any statistically significant correlations with synovial protein concentrations. TPC was positively associated with intraarticular bFGF levels and pain strength (p < 0.01), both indicators for osteoarthritis (OA). Correlating with the negative relation of TPC and BMP-2, subjective knee function after 1 year was positively linked to intraarticular BMP-2 concentrations (p < 0.001). Similarly, expression of collagen type II indicated a favorable clinical result reaching statistical significance in case of pain strength (p < 0.01). Initially increased bFGF levels and CD44 expression indicated a worse clinical outcome after 1 year (IKDC, Lysholm Scores, pain strength). Surface expression of CD44 on chondrocytes used for ACI was negatively associated with synovial BMP-2 and positively to TPC and bFGF indicating catabolic synovial conditions. These correlations were also reflected by clinical outcome parameters.

A non-randomized controlled clinical trial on autologous chondrocyte implantation (ACI) in cartilage defects of the medial femoral condyle with or without high tibial osteotomy in patients with varus deformity of less than 5°.

PURPOSE: High tibial osteotomy (HTO) is a recommended concomitant surgery when treating cartilage lesions of the medial femoral condyle (MFC). Varus deformities of 5° and more were considered an indication for HTO in patients with cartilage defects. This study compares clinical outcome in patients with ACI and concomitant varus deformity of <5° with or without additional HTO. METHODS: 43 patients with isolated cartilage defect of the MFC and varus deformity between 1° and 5° (mean age 39.14 ± 8.35 years; mean varus deformity 2.84 ± 1.19°) were included (follow-up 71.88 ± 23.99 months). Group A (n = 19) was treated with ACI and additional HTO; group B (n = 24) received ACI only. Survival rate in terms of absence of the need of reintervention was defined as main outcome parameter. In the subgroup without reintervention, functional outcome (KOOS and WOMAC) was evaluated. RESULTS: Overall rate of reintervention was 12 (27.9 %). Survival was significantly higher in group A (group A 89.5 %, group B 58.33 %; p = 0.023). Although a trend for better clinical outcome was observed for group A in the subgroup without reintervention, this observation lacked statistical significance (KOOS(symptoms) group A 73.23, group B 59.64; p = 0.274). CONCLUSION: While there is general consensus for treating varus deformities of >5° in patients with cartilage lesions of the medial femoral condyle, HTO also leads to a reduced rate of reinterventions and longer survival rates in patients with varus deformities of <5°.

Paget disease of the spine: an evaluation of 101 patients with a histomorphometric analysis of 29 cases.

INTRODUCTION: Paget's disease of bone (PDB) is the second most frequent metabolic bone disease with the spine being a common site of manifestation. Still, neither the disease's etiology nor reasons for its manifestation at preferred skeletal sites are understood. The aim of the current study was therefore to perform a histologic and histomorphometric analysis of PBD biopsies of the spine to achieve a more detailed understanding concerning PDB activity and characteristics. MATERIALS AND METHODS: Out of 754 cases with histologically proven PDB, 101 cases were identified to have involvement of the spine. A total of 29 individual vertebral body biopsies were available for histologic and histomorphometric analysis and were compared to age- and sex-matched spinal bone specimens obtained from skeletal-intact individuals at autopsy. Histomorphometric results were correlated with vertebral body height, disease location and iliac crest biopsies. RESULTS: In the majority of patients, PDB was located in the lumbar spine (62.2%). The cervical spine was affected in 8.2% of all cases with involvement of the second vertebral body (C2) in every other case. In comparison to age-matched individuals, histomorphometric analysis of vertebral body biopsies revealed a significant increase both in trabecular bone volume as well as osteoid parameters. In comparison to histomorphometric data obtained for extra-spinal skeletal locations affected by PDB (iliac crest), no differences in bone micro-architecture or disease activity were observed. CONCLUSION: Disease activity in terms of osteoblast and osteoclast number does not appear to be significantly associated with disease location when spinal and iliac bone biopsies are compared. However, a positive correlation between vertebral body height and density in skeletal-intact individuals and disease incidence was observed leading to the conclusion that vertebral body height and possibly at least the spine bone volume together with bone density might play an important role in the incidence of PDB.

Comparison of arthroscopic and open assessment of size and grade of cartilage defects of the knee.

PURPOSE: The purpose of our study was to compare arthroscopic versus open measurement of cartilage defects and determination of defect grade according to the International Cartilage Repair Society (ICRS) classification. METHODS: Arthroscopic determination of defect size and grade according to the ICRS classification of 450 focal cartilage defects in 407 patients who underwent autologous chondrocyte implantation was compared with definite findings at the time of open knee surgery. Results were analyzed based on defect location, defect size, and experience of the treating surgeon. RESULTS: Open evaluation of all cartilage defects showed a mean size of 4.54 ± 2.11 cm², whereas arthroscopic determination resulted in a significantly larger mean defect size of 5.69 ± 1.81 cm² (P < .001, r = 0.757). This observation was found in all subgroups concerning defect location and experience of the treating surgeon (P < .001). Overestimation was pronounced among inexperienced surgeons (all P < .01) and in smaller defects (P < .01). Concerning grading of the defect according to the ICRS classification, there was a consensus in 80.9% of the cases when arthroscopic grading was compared with open grading. No differences were found based on defect location or experience of the treating surgeon (P > .05). CONCLUSIONS: Although a high correlation was found between arthroscopic and open evaluation of the cartilage defect size, there is a significant overestimation of the cartilage defect size during arthroscopy. This observation is independent of defect location. Smaller defects and inexperienced surgeons are factors that make an overestimation of defect size more likely. Arthroscopic detection and estimation of the full-thickness cartilage defects according to the ICRS classification seem reliable. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

In vitro cell quality of articular chondrocytes assigned for autologous implantation in dependence of specific patient characteristics.

OBJECTIVE: Autologous chondrocyte implantation (ACI) is a well-established therapeutic option for the treatment of cartilage defects of the knee joint. Since information concerning the cellular aspects of ACI is still limited, the aim of the present study was to investigate relevant differences between chondrocyte quality after in vitro cultivation and possible correlations with patient-specific factors. DESIGN: Cell quality of 252 consecutive ACI patients was assessed after chondrocyte in vitro expansion by determination of the expression of cartilage relevant surface marker CD44 and cartilage-specific differentiation markers (aggrecan and collagen type II). All cell quality parameters were correlated with patient-specific parameters, such as age, size and defect location, number of defects and grade of joint degeneration according to the Kellgren-Lawrence classification. RESULTS: Neither the expression of CD44, aggrecan or collagen type II nor cell density or viability after proliferation seemed to correlate with the grade of joint degeneration, defect aetiology or patient gender. However, chondrocytes harvested from the knee joints of patients at less than 20 years of age showed significantly higher expression rates of cartilage-specific markers when compared to older patients' chondrocytes. CONCLUSIONS: The present study identifies relevant differences concerning chondrocyte quality after in vitro expansion in a highly preselected study population of 252 patients that from a surgical point of view were eligible for ACI. With the exception of patients aged 20 years or younger, no patient-specific parameters could be identified which might allow anticipation of cell quality in individual patients.

Skeletal analysis and comparison of bog bodies from Northern European peat bogs.

Although numerous bodies were deposited in Western European bogs in the past centuries, few were found and underwent archeological analysis. No studies comparing skeletal structure and mineralization of bog bodies from different ages have been performed to this day. Therefore, the aim of this study was to analyze and compare skeletal features and specifics of the human remains of three bog bodies from the Iron and Middle Ages found in Northern European peat bogs. Demineralization due to the acidic environment in peat bogs was comparably pronounced in all three bodies. Still, the macroscopic state of skeletal preservation was excellent. In addition to contact radiography, we used peripheral quantitative computed tomography to measure cortical bone mineral density. The conservation of skeletal three-dimensional microstructural elements was assessed by high-resolution microcomputed tomography analysis. These techniques revealed severe differences in bone mineral density and enabled us to determine handedness in all three bodies. Additionally, unique skeletal features like intravital bone lesions, immobilization osteoporosis, and Harris lines were found. A deformity of the left femoral head was observed which had the typical appearance of an advanced stage of Legg-Calve-Perthes disease. This study gives detailed insight into the skeletal microstructure and microarchitecture of 800- to 2,700-year-old bog bodies. Skeletal analysis enables us to draw conclusions not only concerning changes in the acidic environment of the bog, but also serves as a diagnostic tool to unravel life circumstances and diseases suffered by humans in the Iron and Middle Ages.

Standardized cartilage biopsies from the intercondylar notch for autologous chondrocyte implantation (ACI).

Autologous chondrocyte implantation (ACI) is an established therapy for the treatment of cartilage defects across the knee joint. Even though different techniques for initial biopsy have been described, the exact location, depth, and volume of the biopsy are chosen individually by the treating surgeon. This study evaluated 252 consecutive cartilage biopsies taken from the intercondylar notch with a standardized hollow cylinder system for the isolation and in vitro cultivation of human chondrocytes assigned to ACI. All biopsies were assessed for weight of total cartilage obtained, cartilage biopsy weight per cylinder, biopsy cylinder quality, and initial cell count after digestive cellular isolation as well as cell vitality. Parameters were correlated with individual patient parameters. Mean patient age was 35.1 years (median 35.9; range 14.7-56.4). Adequate amounts of cartilage assigned to chondrocyte in vitro cultivation could be harvested in all cases. The mean overall biopsy weight averaged 75.5 mg (SD +/- 44.9) and could be identified as main factor for initial cell number (mean 1.05E+05; SD +/- 7.44E+04). No correlation was found between the initial cell count and patient age (correlation coefficient r = 0.005) or grade of joint degeneration (r = 0.040). Concerning cell viability, a total of 4.4% (SD + 3.0) of the chondrocytes harvested were apoptotic. Cartilage biopsies from the intercondylar notch using a standardized hollow cylinder system provides a reliable, safe, and successful method to obtain articular cartilage for further in vitro cultivation of articular chondrocytes to achieve autologous chondrocyte transplantation.

Revision Surgery After Cartilage Repair: Data From the German Cartilage Registry (KnorpelRegister DGOU).

BACKGROUND: Various operative strategies have been introduced to restore the integrity of articular cartilage when injured. The frequency of revision surgery after cartilage regenerative surgery remains incompletely understood. PURPOSE/HYPOTHESIS: The purpose of this study was to identify the reasons for revision surgery after cartilage regenerative surgery of the knee. We hypothesized that in a large patient cohort, revision rates would differ from those in the current literature. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 2659 complete data sets from the German Cartilage Registry were available for analyses. In brief, baseline data were provided by the attending physician at the time of index surgery. Follow-up data were collected using a web-based questionnaire inquiring whether patients had needed revision surgery during follow-up, which was defined as the endpoint of the present analysis. RESULTS: A total of 88 patients (3.3%) reported the need for revision surgery as early as 12 months postoperatively. Among the most common causes were arthrofibrosis (n = 27) and infection (n = 10). Female patients showed a significantly greater complication rate (4.5%) when compared with male patients (2.6%; P = .0071). The majority of cartilage lesions were located at the medial femoral condyle (40.2%), with a mean defect size of 3.5 ± 2.1 cm2. Neither the location nor defect size appeared to lead to an increased revision rate, which was greatest after osteochondral autografts (5.2%) and autologous chondrocyte implantation (4.6%). Revision rates did not differ significantly among surgical techniques. Chi-square analysis revealed significant correlations between the number of previous joint surgeries and the need for revision surgery (P = .0203). Multivariate regression analysis further confirmed sex and the number of previous surgeries as variables predicting the need for early revision surgery. CONCLUSION: The low early revision rates found in this study underline that today's cartilage repair surgeries are mostly safe. Although invasiveness and techniques differ greatly among the procedures, no differences in revision rates were observed. Specific factors such as sex and the number of previous surgeries seem to influence overall revision rates and were identified as relevant risk factors with regard to patient safety.

The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover.

Skeletal pathologies are frequently observed in lysosomal storage disorders, yet the relevance of specific lysosomal enzymes in bone remodeling cell types is poorly defined. Two lysosomal enzymes, ie, cathepsin K (Ctsk) and Acp5 (also known as tartrate-resistant acid phosphatase), have long been known as molecular marker proteins of differentiated osteoclasts. However, whereas the cysteine protease Ctsk is directly involved in the degradation of bone matrix proteins, the molecular function of Acp5 in osteoclasts is still unknown. Here we show that Acp5, in concert with Acp2 (lysosomal acid phosphatase), is required for dephosphorylation of the lysosomal mannose 6-phosphate targeting signal to promote the activity of specific lysosomal enzymes. Using an unbiased approach we identified the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), mutated in mucopolysaccharidosis type VI (MPS-VI), as an osteoclast marker, whose activity depends on dephosphorylation by Acp2 and Acp5. Similar to Acp2/Acp5-/- mice, Arsb-deficient mice display lysosomal storage accumulation in osteoclasts, impaired osteoclast activity, and high trabecular bone mass. Of note, the most prominent lysosomal storage accumulation was observed in osteocytes from Arsb-deficient mice, yet this pathology did not impair production of sclerostin (Sost) and Fgf23. Because the influence of enzyme replacement therapy (ERT) on bone remodeling in MPS-VI is still unknown, we additionally treated Arsb-deficient mice by weekly injection of recombinant human ARSB from 12 to 24 weeks of age. We found that the high bone mass phenotype of Arsb-deficient mice and the underlying bone cell deficits were fully corrected by ERT in the trabecular compartment. Taken together, our results do not only show that the function of Acp5 in osteoclasts is linked to dephosphorylation and activation of lysosomal enzymes, they also provide an important proof-of-principle for the feasibility of ERT to correct bone cell pathologies in lysosomal storage disorders. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Return to Sports Activity and Work After Autologous Chondrocyte Implantation of the Knee: Which Factors Influence Outcomes?

BACKGROUND: Autologous chondrocyte implantation (ACI) has been associated with satisfying results in everyday activities. Clinical results after ACI treatment of femorotibial lesions are superior in comparison with patellofemoral lesions. There is limited information regarding at which level recreational, amateur, and professional athletes can resume sports and physical activities as well as work after ACI and what parameters influence return to work and sports. HYPOTHESIS: Return to sports activity and work is dependent on defect characteristics such as location and size. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 130 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI between June 2000 and October 2007 were retrospectively studied by an established questionnaire that assessed sports-specific questions such as frequency, duration, and intensity. Engagement in 32 different sports disciplines was evaluated. In addition, work-specific data were evaluated according to classifications established by the REFA Association. Results were evaluated depending on patient- and defect-specific parameters. RESULTS: The mean ± SD patient age at ACI was 36.2 ± 9.2 years, with a mean defect size of 4.4 ± 1.7 cm(2). Defects were located at the femorotibial compartment in 55.7% of cases, whereas lesions of the patellofemoral compartment were found in 44.3%. Mean duration of inability to work after ACI was 13.6 ± 11.0 weeks and did not appear to be influenced by patient age. Defect location and defect size did not appear to significantly influence return-to-work rates, but work intensity before surgery significantly influenced return-to-work rates and duration of absence from work. Workplace adaptations were necessary in only 9.2% of cases postoperatively. With regard to postoperative sports activity, 73.1% of patients were able to return to sports. Neither defect location nor size significantly influenced return to physical activity. Patients participated in a mean of 2.3 different sports during their lifetime. Both duration of exercise and number of sessions per week significantly decreased from before to after surgery. Detailed analysis of 32 different sporting activities revealed that high-impact as well as start-stop sports were generally abandoned in favor of endurance and low-intensity exercises. A lifetime level of competitiveness was maintained in 31.3% of cases, while return to elite sports at the time of the survey became highly unlikely (0.8%). CONCLUSION: The study results illustrate that treatment of articular cartilage defects of the knee joint leads to satisfactory results concerning everyday activities. With the exception of physical labor, no essential adaptations needed to be made at work. Regarding sports activity, return to low- and moderate-intensity levels appears realistic in the majority of cases, whereas the likelihood of returning to activities with high stress applied on the knee joint is low. Neither defect location nor size appears to significantly influence postoperative sports activity or return-to-work rates.

Clinical outcomes after cell-seeded autologous chondrocyte implantation of the knee: when can success or failure be predicted?

BACKGROUND: Autologous chondrocyte implantation (ACI) has been associated with satisfying results. Still, it remains unclear when success or failure after ACI can be estimated. PURPOSE: To evaluate the clinical outcomes of cell-seeded collagen matrix-supported ACI (ACI-Cs) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospectively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee (IKDC) score and Lysholm knee score. RESULTS: Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5, respectively, to 79.1 and 83.5, respectively, at 36 months. Only half the patients (46.6%) with poor IKDC scores (ie, <70) at 6 months postoperatively showed continued poor or fair scores at 36 months' follow-up. The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81, respectively, when scores were persistent at 12 and 24 months. All 3 patients (100%) with good IKDC scores (ie, 81-90) at 6 months after surgery showed constant or even improved scores at 36 months' follow-up. Ninety-one percent of patients with good and excellent scores at 12 months and 83% of patients with good and excellent scores at 24 months (a total of 23 and 37 patients, respectively) were able to maintain these scores at 36 months' follow-up. Similar results were obtained for the Lysholm score. CONCLUSION: With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery, the technique described here appears to lead to satisfying and stable clinical results. This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI. In patients with good/excellent scores shortly after surgery, deterioration of the knee's condition is rarely found. For patients with poor and fair postoperative scores, clinical outcomes are more difficult to predict, especially during the first year after the procedure.

Metaphyseal bone formation induced by a new injectable ß-TCP-based bone substitute: a controlled study in rabbits.

PURPOSE: Adequate filling of bone defects still poses a challenge in every day clinical work. As many bone defects are irregularly shaped the need for appropriate scaffolds reaching the complete defect surface are great. The purpose of this pre-clinical pilot study was to investigate the handling, biocompatibility, biodegradation and osteoconductivity of a new pasty bone substitute (pure phase ß-TCP, hyaluronic acid, methylcellulose) in bone tissue. METHODS: In an unilateral tibial defect model the peri-implant and bone tissue response to the new pasty bone substitute was tested in New Zealand white rabbits for up to 24 weeks compared to empty controls. Analysis included HR-pQCT scans, histomorphometric evaluation and quantification of vascularization of un-decalcified histological slices. RESULTS: After 1 week the experimental group presented significantly higher new bone volume fraction (p = 0.021) primarily consisting of immature bone matrix and higher vessel density compared to controls (p = 0.013). After 4 weeks bone formation was not significantly different to controls but was distributed more evenly throughout the defect. Bone matrix was now mineralized and trabeculae were thicker than in controls (p = 0.002) indicating faster intramedullary bone maturation. Controls presented extensive periosteal bone formation, major fibrous tissue influx and high vascularization. After 12 and 24 weeks there was no new bone detectable. There were no severe signs of inflammation at all time points. CONCLUSION: The substitute showed an early induction of bone formation. It promoted accelerated intramedullary bone repair and maturation and prevented periosteal bone formation indicating its potential use for reconstructive surgery of bone defects.

CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals.

Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl(-) /H(+) exchanger CLC-7 and the a3 subunit of the vacuolar H(+) -ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n=1), CLCN7 (n=3), or TCIRG1 (n=3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A-dependent or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis.