[Gout (ICD 10: M10): a retrospective analysis of the data from the histopathological arthritis register of the DGORh]. / Gicht (ICD-10: M10): Eine retrospektive Analyse der Daten des histopathologischen Arthritisregisters der DGORh.

BACKGROUND: Gout is considered to be the most common inflammatory arthritis worldwide. The histopathological arthritis register of the German Society for Orthopedic Rheumatology (DGORh) was founded in 2018. The aim of this register is a systematic collection of histopathological data on joint pathologies. As part of a master's thesis in medicine at the Sigmund Freud Private University (Vienna, Austria) the data on gout cases were retrospectively analyzed. OBJECTIVE: The objective of this analysis was to determine the prevalence of gout, the localizations of gout in the musculoskeletal system and the sensitivity of clinical gout diagnostics. MATERIAL AND METHODS: In cooperation with the Medical Treatment Center for Histology, Cytology and Molecular Diagnostics in Trier, Germany (MVZ-HZMD-Trier GmbH; Germany), tissue samples from 190 different orthopedic clinics and practices were analyzed and 7595 datasets were collected and stored in an arthritis register created by the DGORh. All gout cases stored between 1 January 2018 and 20 January 2020 were eligible for retrospective analysis (N = 102). RESULTS: The prevalence of gout was calculated at 1.34%. Of 108 histopathologically confirmed urate crystal depositions and gout granulomas, 76 were found in the lower extremities (70.37%), 30 in the upper extremities (27.78%) and 2 in the spinal joints (1.85%). The sensitivity of clinical gout diagnostics could be determined at 73.53%. CONCLUSION: Gout affects different anatomical regions with the first metatarsophalangeal joint being the main localization site. The sensitivity of clinical gout diagnostics was determined at 73.53%. These results emphasize the importance of histopathology in gout diagnostics.

Diagnostic value of open incisional biopsies in suspected, difficult-to-diagnose periprosthetic hip joint infection prior to revision surgery.

INTRODUCTION: Prior to revision of total hip arthroplasty (THA), low-grade chronic periprosthetic joint infection (PJI) is often difficult to diagnose. We aimed to determine the diagnostic accuracy of open incisional tissue biopsy for the prediction of PJI prior to THA revision in cases with culture-negative or dry tap joint aspirates. MATERIALS AND METHODS: This retrospective single-center study includes 32 consecutive THA revision cases with high clinical suspicion of low-grade chronic PJI of the hip with culture-negative or dry tap joint aspirates and without systemic signs of infection. Open incisional biopsy (OIB) was performed prior to revision surgery. Periprosthetic tissue samples were analyzed by microbiology and histopathology for PJI. During definitive revision arthroplasty, identical diagnostics were repeated. Results from both procedures were compared and sensitivity, specificity, positive and negative predictive values of OIB for the final diagnosis were calculated. RESULTS: Average age at revision was 69.3 ± 13.5 years. The sensitivity of the OIB procedure was 80% (microbiology), 69% (histology) and 82% for combined analyses (microbiology and histology). Specificity of OIB was 80% (microbiology), 94% (histology) and 60% for combined analyses. CONCLUSIONS: Open tissue biopsy performed in cases with culture-negative or inconclusive synovial fluid aspirates prior to revision of THA has limited diagnostic accuracy for the prediction of PJI. The procedure does not reliably close the diagnostic gap in a substantial number of cases. In this difficult patient population, risk of an open procedure may outweigh benefits and alternative less invasive methods should be considered for the preoperative diagnosis of PJI.

Chronic pain in osteoarthritis of the hip is associated with selective cognitive impairment.

INTRODUCTION: Chronic pain of various origin is known to be associated with selective cognitive impairment. Osteoarthritis (OA) of the hip is one of the leading causes of chronic pain in the adult population, but its association with cognitive performance has not been evaluated. Here, we investigate the effect of chronic pain due to unilateral OA of one hip and no further source of chronic pain on cognitive performance. MATERIALS AND METHODS: A neuropsychological test battery, consisting of the Mini-Mental State Examination, Rey-Osterrieth complex figure test, Rivermead behavioural memory test, d2 test of attention, and F-A-S test was applied in 148 patients and 82 healthy pain-free control individuals. The influence of potentially confounding factors such as depression and anxiety was examined. RESULTS: Patients with OA of the hip showed decreased performance in specific neuropsychological tests. Performance in verbal and visual short-term and long-term memory and selective attention tests was significantly poorer compared to healthy controls. Whereas the executive functions "updating", "set shifting", "response inhibition" and "reflection" appear intact, "problem solving" and "planning" were impaired. None of the confounders showed any influence on cognitive performance in both study groups. CONCLUSION: We conclude that chronic pain secondary to end-stage hip OA is associated with selective cognitive impairment. Future studies are required to investigate the effect of total hip arthroplasty on cognitive performance.

Impact of polyethylene glenoid cementation technique on cement mantle integrity and stability after cyclic loading: a computed tomography and biomechanical study.

BACKGROUND: There are no generally accepted guidelines for polyethylene (PE) glenoid component cementation techniques. In particular, it is not known whether the backside of a PE glenoid should be fully or partially cemented-or not cemented at all. We hypothesized that cementing techniques would have an impact on cement mantle volume and integrity, as well as biomechanical stability, measured as micromotion under cyclic loading. METHODS: To address our hypothesis, 3 different cementation techniques using a single 2-peg PE glenoid design with polyurethane foam were compared regarding (1) the quality and quantity of the cement mantle and (2) biomechanical stability after cyclic loading in vitro. Eight identically cemented glenoids per group were used. Group A underwent cement application only into the peg holes, group B received additional complete cement mantle application on the backside of the glenoid, and group C received the same treatment as group B but with additional standardized drill holes in the surface of the glenoid bone for extra cement interdigitation. All glenoids underwent cyclic edge loading by 105 cycles according to ASTM F2028-14. Before and after loading, cement mantle evaluation was performed by XtremeCT and biomechanical strength and loosening were evaluated by measuring the relative motion of the implants. RESULTS: The cement mantle at the back of the implant was incomplete in group A as compared with groups B and C, in which the complete PE backside was covered with a homogeneous cement mantle. The cement mantle was thickest in group C, followed by group B (P = .006) and group A (P < .001). We did not detect any breakage of the cement mantle in any of the 3 groups after testing. Primary stability during cyclic loading was similar in all groups after the "running-in" phase (up to 4000 cycles). Gross loosening did not occur in any implant. CONCLUSIONS: Coverage of the PE glenoid with cement was reproducible in the fully cemented groups (ie, groups B and C) as compared with relevant cement defects in group A. The addition of cement to the back of the PE glenoid and additional drill holes in the glenoid surface did not improve primary stability in the tested setting.

Hip abductor tendon pathology visualized by 1.5 versus 3. 0 Tesla MRIs.

INTRODUCTION: Hip abductor tendinopathies are becoming increasingly recognized as clinically relevant disorders. However, knowledge about prevalence of abductor tendinopathies and associated disorders of adjacent hip articular and periarticular structures is limited. In this context, the relative diagnostic value of 1.5-T vs. 3.0-T MRI magnets has not been studied yet. MATERIALS AND METHODS: Pelvic MRI scans of 1000 hips from 500 consecutive unselected patients (341 in 3.0-T/159 in 1.5-T magnets, with standardized scanning protocols over the entire study period) were analysed for the detection of abductor tendinosis, calcifying tendinitis, partial or full-thickness tears of the M. gluteus medius (GMed) and/or -minimus (GMin) and trochanteric bursitis (TB). The occurrence of these lesions was correlated to the presence of muscle atrophy (MA) of GMed/GMin, hip joint effusion (JE) and osteoarthritis (OA). RESULTS: Peritrochanteric lesions were observed with a prevalence of 31.4% of all patients (22.3% of all hips). TB occurred almost exclusively in the presence of GMed/GMin tendinopathies. Compared to overall prevalence, patients with MA displayed lesions of GMed/GMin or TB in 70%, patients, with OA in 30% and with JE in 23%. These lesions occurred significantly more often ipsilateral to MA and OA than contralateral (MA: 76.8% vs. 23.2%, p < 0.001; OA: 64.4% vs. 35.6%, p = 0.03; JE: 62.7% vs. 37.3%, p = 0.08). Significantly more tendon lesions, in particular specific radiological diagnoses like partial/full-thickness tears, were detected by 3.0-T MRI than by 1.5 T (p = 0.019). CONCLUSIONS: Peritrochanteric lesions are a prevalent pathology that should specifically be looked for, preferably by 3.0-T MRI, independent of concomitant hip joint pathology.

Total Hip Arthroplasty in Multiple Sclerosis. / Hüftendoprothetik bei multipler Sklerose.

Systemic neurological disease represents a risk factor for complications after total hip arthroplasty (THA), especially for dislocation, infections, gait disorders and fall-related periprosthetic fractures. There is little specific literature on total hip arthroplasty in patients with multiple sclerosis. However, increased revision rates have been reported, which are in part due to dislocations. Implants with increased dislocation safety, e.g. tripolar acetabular systems, can represent a reasonable alternative. Due to gait disorders and a higher prevalence of osteoporosis, specific osteological evaluation and treatment should be considered to prevent periprosthetic fractures. This short review summarizes the current literature on total hip arthroplasty in patients with multiple sclerosis.

General synovitis score and immunologic synovitis score reflect clinical disease activity in patients with advanced stage rheumatoid arthritis.

The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = <0.001, r = 0.68, p = <0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response.

Calcification of the acetabular labrum of the hip: prevalence in the general population and relation to hip articular cartilage and fibrocartilage degeneration.

BACKGROUND: Meniscal calcification is considered to play a relevant role in the pathogenesis of osteoarthritis of the knee. Little is known about the biology of acetabular labral disease and its importance in hip pathology. Here, we analyze for the first time the calcification of the acetabular labrum of the hip (ALH) and its relation to hip cartilage degeneration. METHODS: In this cross-sectional post-mortem study of an unselected sample of the general population, 170 ALH specimens and 170 femoral heads from 85 donors (38 female, 47 male; mean age 62.1 years) were analyzed by high-resolution digital contact radiography (DCR) and histological degeneration grade. The medial menisci (MM) from the same 85 donors served as an intra-individual reference for cartilage calcification (CC). Scanning electron microscopy (SEM), energy dispersive analysis (ED) and Raman spectroscopy were performed for characterization of ALH CC. RESULTS: The prevalence of CC in the ALH was 100% and that in the articular cartilage of the hip (ACH) was 96.5%. Quantitative analysis revealed that the amount of ALH CC was higher than that in the ACH (factor 3.0, p < 0.001) and in the MM (factor 1.3, p < 0.001). There was significant correlation between the amount of CC in the fibrocartilage of the left and right ALH (r = 0.70, p < 0.001). Independent of age, the amount of ALH CC correlated with histological degeneration of the ALH (Krenn score) (r = 0.55; p < 0.001) and the ACH (Osteoarthritis Research Society International (OARSI), r = 0.69; p < 0.001). Calcification of the ALH was characterized as calcium pyrophosphate dihydrate deposition. CONCLUSION: The finding that ALH fibrocartilage is a strongly calcifying tissue is unexpected and novel. The fact that ALH calcification correlates with cartilage degeneration independent of age is suggestive of an important role of ALH calcification in osteoarthritis of the hip and renders it a potential target for the prevention and treatment of hip joint degeneration.

Labral calcification in end-stage osteoarthritis of the hip correlates with pain and clinical function.

The acetabular labrum of the hip (ALH) is recognized as a clinically important structure, but knowledge about the pathophysiology of this fibrocartilage is scarce. In this prospective study we determined the prevalence of ALH calcification in patients with end-stage osteoarthritis (OA) and analyzed the relationship of cartilage calcification (CC) with hip pain and clinical function. Cohort of 80 patients (70.2 ± 7.6years) with primary OA scheduled for total hip replacement. Harris Hip Score (HHS) was recorded preoperatively. Total ALH and femoral head (FH) were sampled intraoperatively. CC of the ALH and FH was analyzed by high-resolution digital contact radiography. Histological degeneration of the ALH (Krenn-Score) and FH (OARSI-Score) was determined. Multivariate linear regression model and partial correlation analyses were performed. The prevalence of cartilage calcification both in the ALH and FH was 100%, while the amount of CC in the ALH was 1.55 times higher than in the FH (p < 0.001). There was a significant inverse regression between the amount of calcification of both the ALH and the FH and preoperative HHS (ßALH = -2.1, p = 0.04), (ßFH = -2.9, p = 0.005), but pain was influenced only by ALH calcification (ßALH = -2.7, p = 0.008). Age-adjusted, there was a significant correlation between cartilage calcification and histological degeneration (ALH:rs = 0.53, p < 0.001/FH: rs = 0.30, p = 0.007). Fibrocartilage and articular cartilage calcification are inseparable pathological findings in end-stage osteoarthritis of the hip. Fibrocartilage calcification is associated with poor and painful hip function. CLINICAL SIGNIFICANCE: ALH fibrocartilage appears to be particularly prone to calcification, which may explain higher pain levels in individuals with a high degree of ALH calcification independent of age and histological degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1248-1255, 2018.

Differential effects of Calca-derived peptides in male mice with diet-induced obesity.

Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (αCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr-/- (encoding the calcitonin receptor, CTR), Calca-/-, and αCGRP-/- mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks. HFD-induced pathologies were assessed by glucose tolerance, plasma cytokine and lipid markers, expression studies and histology. We found that DIO in mice lacking the CTR resulted in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation compared to wildtype littermates. Furthermore, CTR-deficient mice were characterized by dyslipidemia and elevated HDL levels. In contrast, mice lacking Calca were protected from DIO, NASH and adipose tissue inflammation, and displayed improved glucose tolerance. Mice exclusively lacking αCGRP displayed a significantly less improved DIO phenotype compared to Calca-deficient mice. In summary, we demonstrate that the CT/CTR axis is involved in regulating plasma cholesterol levels while Calca, presumably through PCT, seems to have a detrimental effect in the context of metabolic disease. Our study provides the first comparative analyses of the roles of Calca-derived peptides and the CTR in metabolic disease.

Microcalcification of lumbar spine intervertebral discs and facet joints is associated with cartilage degeneration, but differs in prevalence and its relation to age.

Cartilage calcification (CC) is associated with degeneration in non-vertebral joints, but little is known about CC and lumbar vertebral joints. The goal of this study was to analyze the prevalence of CC in lumbar facet joints (FJ) and intervertebral discs (IVD) and its relation to cartilage degeneration and age in a non-selected cohort of the general population. The segment L4/5 of 85 consecutive donors (mean age 61.9 years) was analyzed by high-resolution imaging digital-contact radiography (DCR). Quantification was achieved by measuring CC in % of total cartilage area. Histological degeneration of FJs and IVDs was determined by OARSI and Boos scores. Prevalence of CC was 36.5% for FJ (95%CI (0.26, 0.48)) and 100% for IVD (95%CI (0.96, 1.00)). The amount of IVD CC (3.36% SD ± 7.14) was 16.3 times higher (p < 0.001) than that of the FJ (0.23% SD ± 0.53) and independent of each other (p = 0.07). The amount of FJ CC correlated significantly with FJ and IVD degeneration (FJ r = 0.44, p = 0.01, IVD r = 0.49, p = 0.006) while the amount of IVD CC correlated only with IVD degeneration (r = 0.54, p < 0.001). Age correlated with IVD CC (rs = 0.35, p < 0.001), but not FJ CC (rs = 0.04, p = 0.85). We conclude that IVD fibrocartilage is particularly prone to calcification. A causal relationship between lumbar CC and degeneration is possible, but the clear differences in IVD fibrocartilage CC and FJ synovial joint CC in regard to prevalence and in relation to age point to a differential role of CC in single compartments of the respective motion segment in lumbar spine degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2692-2699, 2017.

Hyaline cartilage calcification of the first metatarsophalangeal joint is associated with osteoarthritis but independent of age and BMI.

BACKGROUND: Hyaline cartilage calcification (CC) is associated with osteoarthritis (OA) in hip and knee joints. The first metatarsophalangeal joint (1stMTPJ) is frequently affected by OA, but it is unclear if CC occurs in the 1stMTPJ. The aim of the present study was to analyze the prevalence of CC of the 1stMTPJ in the general population by high-resolution digital contact radiography (DCR) and to determine its association with histological OA severity, age and body mass index (BMI). METHODS: 168 metatarsal heads of 84 donors (n = 47 male, n = 37 female; mean age 62.73 years, SD ±18.8, range 20-93) were analyzed by DCR for the presence of CC. Histological OA grade (hOA) by OARSI was analyzed in the central load-bearing zone of the first metatarsal head (1st MH). Structural equation modeling (SEM) was performed to analyze the interrelationship between CC, hOA, age and BMI. RESULTS: The prevalence of CC of 1stMH was 48.8 % (41/84) (95 %-CI [37.7 %, 60.0 %]), independent of the affected side (p = 0.42), gender (p = 0.41) and BMI (p = 0.51). The mean amount of CC of one MH correlated significantly with that of the contralateral side (rs = 0.4, 95 %-CI [0.26, 0.52], p < 0.001). The mean amount of CC (in % of total cartilage area) of the MH correlated significantly with the severity of hOA (rs = 0.51, 95 %-CI [0.32, 0.65], p < 0.001). SEM revealed significant associations between CC and hOA (r = 0.74, p < 0.001) and between hOA and age (ß = 0.62, p = 0.001), but not between CC and age (p = 0.15). There was no significant influence of BMI on either CC (p = 0.37) or hOA (p = 0.16). CONCLUSION: The observation that CC of the 1stMH is significantly associated with the severity of OA but independent of age and BMI, suggests an intimate relationship between CC and the pathogenesis of OA, the exact nature of which will have to be explored by future studies.

Articular cartilage calcification of the humeral head is highly prevalent and associated with osteoarthritis in the general population.

Articular cartilage calcification is considered a pathological albeit incompletely understood process which is known to be associated with osteoarthritis of the knee and hip. The goal of this study was to determine the prevalence of articular cartilage calcification of the shoulder as a non-weight-bearing joint and to analyze the interrelationship of calcification with age and histological severity of shoulder osteoarthritis in the general population. In a cross-sectional study of 180 humeral heads from 90 donors (n = 49 male, n = 41 female; mean age 62.7 years [20-93]), cartilage calcification of the humeral head was quantified by digital contact radiography (DCR). Histological OA grade (OARSI) was determined and structural equation modeling (SEM) was used to analyze the interrelationship of cartilage calcification, OARSI and age. The prevalence of articular cartilage calcification was 98.9% (95%CI: [93.96%, 99.97%]) and was independent of gender (p = 0.55). Cartilage calcification of one shoulder correlated significantly with that of the contralateral side (r = 0.61, 95%CI: [0.46, 0.73], p < 0.001). SEM demonstrated significant associations between histological OA grade and cartilage calcification (r = 0.55, p = 0.039), between histological OA grade and age (ß = 0.59, p < 0.001) but not between age and cartilage calcification (ß = 0.24, p = 0.116). In conclusion, the prevalence of shoulder cartilage calcification in the general population is higher than anticipated. The high prevalence, its concomitant bilateral manifestation and the association between the amount of cartilage calcification and OA severity, but not age, suggest that cartilage calcification is a systemically driven process with early onset in life and may be a causative factor in the pathogenesis of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1984-1990, 2016.

Signature of circulating microRNAs in osteoarthritis.

BACKGROUND: Osteoarthritis is the most common form of arthritis and a major socioeconomic burden. Our study is the first to explore the association between serum microRNA levels and the development of severe osteoarthritis of the knee and hip joint in the general population. METHODS: We followed 816 Caucasian individuals from 1995 to 2010 and assessed joint arthroplasty as a definitive outcome of severe osteoarthritis of the knee and hip. After a microarray screen, we validated 12 microRNAs by real-time PCR in the entire cohort at baseline. RESULTS: In Cox regression analysis, three microRNAs were associated with severe knee and hip osteoarthritis. let-7e was a negative predictor for total joint arthroplasty with an adjusted HR of 0.75 (95% CI 0.58 to 0.96; p=0.021) when normalised to U6, and 0.76 (95% CI 0.6 to 0.97; p=0.026) after normalisation to the Ct average. miRNA-454 was inversely correlated with severe knee or hip osteoarthritis with an adjusted HR of 0.77 (95% CI 0.61 to 0.97; p=0.028) when normalised to U6. This correlation was lost when data were normalised to Ct average (p=0.118). Finally, miRNA-885-5p showed a trend towards a positive relationship with arthroplasty when normalised to U6 (HR 1.24; 95% CI 0.95 to 1.62; p=0.107) or to Ct average (HR 1.30; 95% CI 0.99 to 1.70; p=0.056). CONCLUSIONS: Our study is the first to identify differentially expressed circulating microRNAs in osteoarthritis patients necessitating arthroplasty in a large, population-based cohort. Among these microRNAs, let-7e emerged as potential predictor for severe knee or hip osteoarthritis.

Massive accumulation of osteoclastic giant cells in rapid destructive hip disease.

The term rapid destructive hip disease (RDHD) designates a rare coxarthropathy characterized by a rapid destruction of the femoral head within a few weeks to several months. The etiology and pathogenesis of RDHD are not understood. The goal of this study was to define the histological and histomorphometric hallmarks of RDHD to provide a basis for a deeper understanding of the underlying mechanisms. Fifteen consecutive RDHD patients (mean age 78.9 ± 6.4 years, 14 females) demonstrated the characteristic radiographic appearance of vanishing femoral head bone stock without signs of reactive anabolic changes. Histologic and histomorphometric analyses revealed severe bone resorption with significantly increased numbers of morphologically altered giant osteoclasts, the formation of giant cell granulomas both in bone marrow and the synovium and significantly increased osteoblast numbers and osteoid as compared to controls with primary osteoarthritis (OA). These results suggest that in RDHD, an unknown stimulus leads to a massive activation of osteoclasts and this in turn provokes a reactive increase in osteoblast activity that is too weak to counteract the rapid destruction of the hip, thus providing a rationale for a prospective systematic search for the stimuli upstream of the massively increased osteoclast activation in RDHD.

Hepatic lipase is expressed by osteoblasts and modulates bone remodeling in obesity.

A number of unexpected molecules were recently identified as products of osteoblasts, linking bone homeostasis to systemic energy metabolism. Here we identify the lipolytic enzyme hepatic lipase (HL, encoded by Lipc) as a novel cell-autonomous regulator of osteoblast function. In an unbiased genome-wide expression analysis, we find Lipc to be highly induced upon osteoblast differentiation, verified by quantitative Taqman analyses of primary osteoblasts in vitro and of bone samples in vivo. Functionally, loss of HL in vitro leads to increased expression and secretion of osteoprotegerin (OPG), while expression of some osteoblast differentiation makers is impaired. When challenging energy metabolism in a diet-induced obesity (DIO) study, lack of HL leads to a significant increase in bone formation markers and a decrease in bone resorption markers. Accordingly, in the DIO setting, we observe in Lipc(-/-) animals but not in wild-type controls a significant increase in lumbar vertebral trabecular bone mass and formation rate as well as in femoral trabecular bone mass and cortical thickness. Taken together, we demonstrate that HL expressed by osteoblasts has an impact on osteoblast OPG expression and that lack of HL leads to increased bone mass in DIO. These data provide a novel and completely unexpected molecular link in the complex interplay of osteoblasts and systemic energy metabolism.

Structural brain changes in chronic pain reflect probably neither damage nor atrophy.

Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25±9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6-8 weeks, 12-18 weeks and 10-14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.

Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo.

The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro-computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans.

Serum levels of fetal antigen 1 in extreme nutritional States.

Objective. Recent data suggest that fetal antigen (FA1) is linked to disorders of body weight. Thus, we measured FA1 serum levels in two extreme nutritional states of morbid obesity (MO) and anorexia nervosa (AN) and monitored its response to weight changes. Design. FA1 and insulin serum concentrations were assessed in a cross-sectional study design at defined time points after gastric restrictive surgery for 25 MO patients and 15 women with AN. Results. Absolute FA1 serum levels were within the assay normal range and were not different between the groups at baseline. However, the ratio of FA1/BMI was significantly higher in AN. FA1 was inversely correlated with BMI before and after weight change in AN, but not in MO patients. In addition, MO patients displayed a significant concomitant decrease of FA1 and insulin with the first 25% of EWL, while in AN patients a significant increase of FA1 was observed in association with weight gain. Conclusion. FA1 is a sensitive indicator of metabolic adaptation during weight change. While FA1 serum levels in humans generally do not correlate with BMI, our results suggest that changes in FA1 serum levels reflect changes in adipose tissue turnover.

Osteochondritis dissecans of the tarsal navicular bone: a case report.

Osteochondritis dissecans most often affects the convex articular surfaces of the knee, the elbow, and the ankle joints; other sites of manifestation are very rare. Here we report a case of osteochondritis dissecans of the talonavicular joint affecting the concave part of the tarsal navicular bone in a 22-year-old woman, which was successfully treated by surgery, leading to complete recovery. Early diagnosis and surgery in stages of undamaged cartilage may help to prevent disease progression and the development of disabling osteoarthritis in the physiologically heavily loaded talo-navicular joint.