Klaus-Peter Günther

BMP‐2, BMP‐4, and PDGF‐bb stimulate chemotactic migration of primary human mesenchymal progenitor cells

For bone development, remodeling, and repair; the recruitment of mesenchymal progenitor cells (MPC) and their differentiation to osteoblasts is mandatory. The process of migration is believed to be regulated in part by growth factors stored within the bone matrix and released by bone resorption. In this study, primary human MPCs and to osteoblasts differentiated progenitor cells were examined for chemotaxis in response to human basic fibroblast growth factor (rhbFGF), human transforming growth factor beta 1 (rhTGF‐β1), human platelet derived growth factor bb (rhPDGF‐bb), human bone morphogenetic protein‐2 (rhBMP‐2), and recombinant bone morphogenetic protein‐4 of Xenopus laevis (rxBMP‐4) from 0.001 to 1.0 ng/ml each. The results of migration were expressed as a chemotactic index (CI). Migration of primary human progenitor cells was stimulated by rhBMP‐2, rxBMP‐4, and rhPDGF‐bb in a dose‐dependent manner. The increase of CI was up to 3.5‐fold for rhBMP‐2, 3.6‐fold for rxBMP‐4, and up to 22‐fold for rhPDGF‐bb, whereas rhTGF‐β1 and rhbFGF did not stimulate cell migration in the concentration range tested. In contrast differentiated progenitor cells behave similar to primary human osteoblasts. RhBMP‐2, rhPDGF‐bb, and rhTGF‐β1 stimulated the migration from 2.2 to 2.4‐fold each, while rxBMP‐4 and rhbFGF reached only a CI of 1.7–1.6. The effect of rhBMP‐2, rxBMP‐4, and rhPDGF‐bb as chemoattractive proteins for primary human MPC, including the change in response to growth factors after differentiation suggests a functional role for recruitment of MPCs during bone development and remodeling, as well as fracture healing. J. Cell. Biochem. 87:305‐312, 2002.

Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein

Background: Although osteoarthritis (OA) is thought to derive from defective chondrocyte metabolism and thus inherently lack the large scale systemic response of rheumatoid arthritis, there is increasing interest in the acute phase proteins in OA. Objective: To assess the association between high sensitivity C reactive protein (hsCRP) and severity and extent of OA in patients with advanced hip and knee OA. Methods: Preoperative hsCRP was measured in frozen serum samples from 770 consecutive patients with hip or knee joint replacement due to advanced OA recruited between 1995 and 1996. Pain was measured by a visual analogue scale and the Western Ontario and McMaster Universities OA index (WOMAC). The extent of OA in different joints was assessed clinically and radiographically. Results: The (geometric) mean hsCRP was 2.5 mg/l among all patients. Severity of pain was associated with mean hsCRP (adjusted elevation highest v lowest quintile = 35%, p = 0.01) after controlling for known or suspected predictors of hsCRP, including age, smoking, and body mass index. Neither the bilateral nor the generalised extent of OA, nor any of the dimensions of the WOMAC were associated with mean hsCRP levels. Conclusions: Severity of pain, but not extent of OA, was associated with hsCRP levels in this group of patients with advanced OA. Longitudinal studies with repeated assessments of hsCRP and pain are needed to assess the possible value of hsCRP for monitoring or predicting the clinical course of OA.

International variation in hip replacement rates

Objectives: To summarise epidemiological data on the frequency of hip replacements in the countries of the developed world, especially in countries of the Organisation for Economic Cooperation and Development (OECD), and to investigate whether missing consensus criteria for the indication for total hip replacement (THR) result in different replacement rates. Methods: Country-specific hip replacement rates were collected using the available literature, different data sources of national authorities, and estimates of leading hip replacement manufacturers. Results: According to administrative and literature data sources the reported crude primary THR rate varied between 50 and 130 procedures/100 000 inhabitants in OECD countries in the 1990s. The crude overall hip implantation rate, summarising THR, partial hip replacement, and hip revision procedures, was reported to range from 60 to 200 procedures/100 000 inhabitants in the late 1990s. Moreover, large national differences were seen in the relationship between total and partial hip replacement procedures. Conclusion: The reported differences in hip replacement rates in OECD countries are substantial. They may be due to various causes, including different coding systems, country-specific differences in the healthcare system, in total expenditure on health per capita, in the population age structure, and in different indication criteria for THR.

Prevalence of generalised osteoarthritis in patients with advanced hip and knee osteoarthritis: The Ulm Osteoarthritis Study

OBJECTIVES Different prevalences of generalised osteoarthritis (GOA) in patients with knee and hip OA have been reported. The aim of this investigation was to evaluate radiographic and clinical patterns of disease in a hospital based population of patient subgroups with advanced hip and knee OA and to compare the prevalence of GOA in patients with hip or knee OA, taking potential confounding factors into account. METHODS 420 patients with hip OA and 389 patients with knee OA scheduled for unilateral total joint replacement in four hospitals underwent radiographic analysis of ipsilateral and contralateral hip or knee joint and both hands in addition to a standardised interview and clinical examination. According to the severity of radiographic changes in the contralateral joints (using Kellgren-Lawrence ⩾ grade 2 as case definition) participants were classified as having either unilateral or bilateral OA. If radiographic changes of two joint groups of the hands (first carpometacarpal joint and proximal/distal interphalangeal joints defined as two separate joint groups) were present, patients were categorised as having GOA. RESULTS Patients with hip OA were younger (mean age 60.4 years) and less likely to be female (52.4%) than patients with knee OA (66.3 years and 72.5% respectively). Intensity of pain and functional impairment at hospital admission was similar in both groups, while patients with knee OA had a longer symptom duration (median 10 years) compared with patients with hip OA (5 years). In 41.7% of patients with hip OA and 33.4% of patients with knee OA an underlying pathological condition could be observed in the replaced joint, which allowed a classification as secondary OA. Some 82.1% of patients with hip and 87.4% of patients with knee OA had radiographic changes in their contralateral joints (bilateral disease). The prevalence of GOA increased with age and was higher in female patients. GOA was observed more often in patients with knee OA than in patients with hip OA (34.9% versus 19.3%; OR=2.24; 95% CI: 1.56, 3.21). Adjustment for the different age and sex distribution in both patient groups, however, takes away most of the difference (OR=1.32; 95% CI: 0.89, 1.96). CONCLUSION The crude results confirm previous reports as well as the clinical impression of GOA being more prevalent in patients with advanced knee OA than in patients with advanced hip OA. However, these different patterns might be attributed to a large part to a different distribution of age and sex in these hospital based populations.

Indications for total hip replacement: comparison of assessments of orthopaedic surgeons and referring physicians

Objectives: To analyse differences of opinions on indications for primary total hip replacements (THRs) within and between groups of orthopaedic surgeons and the physicians who refer patients to them. Methods: 22 orthopaedic centres in 12 European countries took part, resulting in a postal survey of 304 orthopaedic surgeons and 314 referring physicians. Each participant was asked to state what importance different domains (pain, functional impairment, physical examination and radiographs) have on their decision to recommend THR and to select the most appropriate level of severity of each symptom or sign for recommending THR. In addition, the participants were asked to prioritise other personal or environmental factors that affect their decision to undertake a THR. Results: Rest pain, pain with activity and functional limitations were the most important criteria for THR, although range of motion and radiographic changes were of least importance. Both similarities and differences were observed within and between groups of surgeons and referring physicians in the overall approach to indications and the most appropriate level of severity of disease for recommending THR. Most surgeons agreed on severity levels in only 4 of 11 items and most referring physicians in only one. Between the groups, major differences occurred with regard to the importance of activities of daily living and the appropriate level of symptoms for THR. In general, compared with surgeons, referring physicians reported that the disease needed to be more advanced to warrant surgery. Conclusion: Currently, no consensus exists on objective indication criteria for THR. The observed differences between the gatekeepers (referring physicians) and surgeons can lead to variations and perhaps inequities in the provision of care.

Proliferation and differentiation rates of a human osteoblast‐like cell line (SaOS‐2) in contact with different bone substitute materials

The aim of our study was to investigate the influence of four bone substitutes on the growth behavior of a human osteoblast-like cell line (SaOS-2) culture: pure alpha tricalcium phosphate (alpha-TCP = BIOBASE), a bioactive glass (bioglass), a neutralized glass-ceramic (GB9N), and solvent dehydrated bone. We established an in vitro cell culture model with three-dimensional scaffolds (cubes of 0.7 x 0.7 x 1.0 cm) of porous bone substitutes to investigate proliferation and differentiation rates of SaOS-2 cells. The cultures were analyzed for individual cell morphology after 5 days of growing using scanning electron microscopy. Fracture preparations of the cubes showed that cells could infiltrate the porous structures, but the cell shapes varied from individual round-shaped cells to wide spread cells and cell clusters, depending on the material. Also, the differentiation of the seeded cells was dissimilar after a 5-day incubation. The specific alkaline phosphatase (ALP) enzyme activity (ALP/DNA) measured in the supernatants of alpha-TCP-grown cells was nine times higher than the lowest activity, as observed by cells incubated on GB9N. Early (Collagen1, ALP) and late marker (osteocalcin, bone sialoprotein) of osteoblastic differentiation were proofed by reverse transcriptase-polymerase chain reaction analysis. Cells grown on bone substitutes and bioglass seem to be less differentiated than alpha-TCP-grown cells, because of noticeably less amounts of osteocalcin and bone sialoprotein. The cultivation on GB9N seems to dedifferentiate the cells, because even the ALP expression was reduced as well. Our results indicate that distinct bone substitutes influence proliferation and differentiation of osteoblastic cells in different manners. These results might influence the selection of an adequate bone substitute for clinical use as well, part from degradative and biomechanical properties.

Reliability and validity of clinical outcome measurements of osteoarthritis of the hip and knee--a review of the literature.

SummaryHigh reliability and validity of clinical rating schemes is crucial for their use as outcome measurements of treatment of hip and knee osteoarthritis. In this paper, we review the empirical evidence on the reliability and validity of commonly used clinical scores. Clinical scores and related reliability and validity studies were identified by systematic literature search. Scores were classified according to the type and joint. Reliability and validity studies were characterized according to design, population, number and qualification of observers, number of measurements, time interval between repeat measurements and results. Reliability and validity studies were reported for only 6 and 15 of the 45 identified clinical scores, respectively. Although comparisons are difficult due to differences in study design, relatively high reliability was reported for most measurements of pain, stiffness, and physical function, while results are less conclusive for clinical signs. Most validity studies focused on the correlation between various scores. Correlation was generally found to be high for overall numerical ratings, but scores often differed with respect to the interpretation of these ratings. Validity has been more comprehensively studied for Lequesnes scores, WOMAC, and ILAS, and these scores have shown satisfactory responsiveness to different treatment effects. Overall, knowledge on reliability and validity of clinical scores of hip and knee osteoarthritis is limited, underlining the need for further properly designed and conducted studies.

Interleukin-1β Induces Different Gene Expression of Stromelysin, Aggrecan and Tumor-Necrosis-Factor-Stimulated Gene 6 in Human Osteoarthritic Chondrocytes in vitro

Objective: To analyze the gene expression of osteoarthritic chondrocytes cultured in alginate after stimulation with interleukin (IL)-1β. Methods: Chondrocytes were isolated from osteoarthritic cartilage obtained during total knee replacement by sequential enzymatic digestion. After suspension in alginate, cells were cultured with and without 100 pg/ml IL-1β. Quantitative RT-PCR reaction was used to estimate the messenger RNA (mRNA) of three different metabolites [tumor-necrosis-factor-stimulated gene 6 (TSG-6), stromelysin-1 (MMP-3) and aggrecan (AGG)]. Results: After having shown the precision of quantitative PCR, this method allowed us to detect IL-1β-induced changes in mRNA of TSG-6, MMP-3 and AGG. MMP-3 was found to be the most abundant transcript, IL-1β induced a 12-fold upregulation of MMP-3 levels compared to control, and 7-fold of TSG-6. The AGG transcript level, indicating anabolic events, was found to be downregulated by between 2- and 3-fold. Conclusions: In our culture system, the response of osteoarthritic chondrocytes to IL-1β is preserved. Therefore, this system might be helpful for further investigation of the influences of drugs, cytokines and growth factors, for example, on the metabolism of chondrocytes at the level of gene transcription as the most basic level of regulation.

Reliability of the Crowe und Hartofilakidis classifications used in the assessment of the adult dysplastic hip

ObjectiveTo assess the inter-observer and intra-observer reliability of two commonly used radiographic classification systems in the evaluation of hip dysplasia in skeletally mature adults.DesignThree observers with different levels of training independently classified 62 dysplastic hips on 51 standard anteriorposterior pelvis radiographs according to the criteria defined by Crowe and by Hartofilakidis. To assess intra-observer reliability, the same radiographs were reviewed 3 months later by the same observers.PatientsAt the time of the radiographic examination, the mean age of the 51 patients had been 54 years (range 18–82 years).ResultsA high correlation concerning the inter- and intra-observer reliability of both systems was demonstrated. Inter-observer reliability displayed a weighted kappa coefficient of 0.82 for the Crowe and 0.75 for the Hartofilakidis classification. Intra-observer reliability showed a kappa coefficient of 0.86 and 0.79, respectively.ConclusionsBoth classification systems can be recommended to compare collectives of adult patients with congenital dysplasia of the hip. However, for future clinical practice, it would be advisable to agree on one universally accepted system as a standard in the literature.

Assessing the prevalence of hand osteoarthritis in epidemiological studies. The reliability of a radiological hand scale

OBJECTIVE The hands are often involved in the osteoarthritic disease process. A radiological grading scale is presented, derived from a published atlas, to assess the prevalence of hand osteoarthritis (OA) involvement in clinical and epidemiological studies and its reproducibility is studied. METHODS This hand scale is based on the radiological feature “joint space narrowing”, which represents the macromorphological process of cartilage loss. Osteophytes and sclerosis are less important unless seen in conjuction with joint space narrowing. Nine individual joints per hand (four proximal interphalangeal joints (PIP), four distal interphalangeal joints (DIP), first carpometacarpal joint (CMC-1)) are scored dichotomously for the presence of OA. To save time and to increase reliability a severity grading of radiological features is not performed. To determine inter-rater and intra-rater reliability of the individual joints and the presence of OA in two separate joint groups (⩾ 2 PIP or DIP and at least one CMC-1, used to define “generalised OA” in the ongoing Ulm Osteoarthritis Study) 50 pairs of anteroposterior hand radiographs were read by two investigators twice within one month. The κ coefficient was calculated to quantify the strength of associations. RESULTS On average five minutes were needed to score one hand radiograph. Both raters were able to reproduce their own readings in all individual joints and for the presence of OA in two separate joint groups after one month. Reliability was highest for the PIP joints (κ: 0.56–1.00) it was slightly lower for the DIP joints (0.38–0.87), for the CMC-1 joints (0.58–0.69) and for OA in two separate joint groups (0.54). The values for inter-rater agreement were good as well, κ coefficients ranged from 0.52 to 0.92. CONCLUSION This grading scale was shown to be reliable within and between readers for all the individual joints as well as for the presence of OA in two separate joint groups. Scoring a limited number of joints dichotomously makes this scale efficient and therefore useful for clinical and epidemiological trials, when dealing with large patient samples.