Objective: Human superficial chondrocytes show distinct spatial organizations, and they commonly aggregate near osteoarthritic (OA) fissures. The aim of this study was to determine whether remodeling or destruction of the spatial chondrocyte organization might occur at a distance from focal (early) lesions in patients with OA.Methods: Samples of intact cartilage (condyles, patellofemoral groove, and proximal tibia) lying distant from focal lesions of OA in grade 2 joints were compared with location‐matched nondegenerative (grade 0–1) cartilage samples. Chondrocyte nuclei were stained with propidium iodide, examined by fluorescence microscopy, and the findings were recorded in a top‐down view. Chondrocyte arrangements were tested for randomness or significant grouping via point pattern analyses (Clark and Evans Aggregation Index) and were correlated with the OA grade and the surface cell densities.Results: In grade 2 cartilage samples, superficial chondrocytes were situated in horizontal patterns, such as strings, clusters, pairs, and singles, comparable to the patterns in nondegenerative cartilage. In intact cartilage samples from grade 2 joints, the spatial organization included a novel pattern, consisting of chondrocytes that were aligned in 2 parallel lines, building double strings. These double strings correlated significantly with an increased number of chondrocytes per group and an increased corresponding superficial zone cell density. They were observed in all grade 2 condyles and some grade 2 tibiae, but never in grade 0–1 cartilage.Conclusion: This study is the first to identify a distinct spatial reorganization of human superficial chondrocytes in response to distant early OA lesions, suggesting that proliferation had occurred distant from focal early OA lesions. This spatial reorganization may serve to recruit metabolically active units as an attempt to repair focal damage.

Die Arbeitsgemeinschaft „Klinische Geweberegeneration“ hat bereits in den Jahren 2004, 2013 und 2016 Empfehlungen in Bezug auf die Indikation für verschiedene knorpelregenerative Verfahren zur Behandlung von Knorpelschäden am Kniegelenk publiziert. Auf Basis neuer wissenschaftlicher Erkenntnisse sollen in der vorliegenden Arbeit diese Empfehlungen auch unter Einbeziehung neuer Behandlungsverfahren aktualisiert werden. Die Einschätzung folgt damit dem Prinzip der besten verfügbaren Evidenz und berücksichtigt über prospektiv randomisierte Studien hinaus auch Studien mit niedrigerem Evidenzniveau. An Stellen fehlender publizierter Evidenz basiert die Entscheidung hier auf einem Konsensusprozess innerhalb der Mitglieder der AG Klinische Geweberegeneration. Das Prinzip der bereits vorausgehend publizierten Arbeiten bleibt auch in den neuen Empfehlungen erhalten. Kleine Knorpelschäden sind nach Ansicht der Arbeitsgruppe für eine Knochenmarkstimulation zugänglich, die matrixassoziierte autologe Chondrozytentransplantation (mACT) ist für größere Knorpelschäden die Methode der Wahl. Auf Basis neuerer Daten wird jedoch die Indikationsgrenze für die mACT auf 2,0 cm² reduziert. Zusätzlich zur arthroskopischen Mikrofrakturierung wird auch die matrixaugmentierte Knochenmarkstimulation in die Empfehlung als Standardverfahren aufgenommen (empfohlene Defektgröße 1–4,5 cm²). Für die Therapie kleinerer osteochondraler Defekte wird neben der osteochondralen Transplantation (OCT) auch die matrixaugmentierte Knochenmarkstimulation empfohlen. Bei größeren Defekten eignet sich die autologe Knorpelzelltransplantation (mACT) in Kombination mit einer Rekonstruktion des subchondralen Knochens. Received: 17 April 2021 Accepted after revision: 02 October 2021 Publication Date: 21 February 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Human chondrocytes isolated from articular cartilage lesions as an alternative cell source to the standard non-weight-bearing notch biopsy site may hold clinical potential for cell-based therapies. The aim was to characterize human AC lesion site chondrocytes, compare them to notch chondrocytes, and to evaluate their re-differentiation potential after monolayer expansion and subsequent 3D alginate bead culture. Lesion chondrocytes from knee joints of 20 patients with ICRS grade 3 and 4 cartilage defects were analyzed ex vivo or cultured in primary alginate bead culture, monolayer expansion, or were re-differentiated in alginate culture following monolayer expansion. The mRNA expression of the types I, II, and X collagen, and the proteoglycan aggrecan was compared between the 4 groups. Additionally, notch chondrocytes of 9 patients were compared to lesion chondrocytes ex vivo. AC lesion chondrocytes displayed ex vivo a non-degenerative phenotype, characterized by a relatively high mRNA expression of aggrecan and type II and X collagen but a low type I collagen expression and a low ratio of type I to II collagen mRNA expression. Compared to notch chondrocytes, the mRNA expression of aggrecan and type II collagen was comparable and the ratio of type I to II collagen mRNA expression was in both groups below 1, indicating a functional chondrocyte phenotype. De-differentiation led to a significantly altered, degenerative mRNA expression profile. Induced re-differentiation in alginate beads after monolayer expansion significantly improved the mRNA expression of aggrecan, the types I and II collagen, and the type I to II collagen ratio, compared to monolayer only. These data suggested that re-differentiating lesion chondrocytes after monolayer expansion in alginate beads resulted in a pool of cells with greater chondrogenic potential, compared to expanded de-differentiated chondrocytes. Collectively, these data suggest that ex vivo and re-differentiated lesion chondrocytes may hold non-utilized clinical potential for the TE of AC.

Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL-6-signaling and IL-6 neutralization on chondrocyte metabolism and the release of IL-6-signaling-related mediators by human chondrocytes. Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL-6 and IL-6/sIL-6R complex as well as neutralization of IL-6-signaling on the metabolism was analyzed. OA chondrocytes showed high basal IL-6 production and release, which was strongly negatively correlated with the production of cartilage-matrix-proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E₂ and matrix metalloproteinase 1 production, decreased Pro-Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL-6-signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL-6 release. Although IL-6 trans-signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL-6 or IL-6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL-6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL-6 correlates with reduced production of cartilage-matrix-proteins.

Posttraumatic osteoarthritis (PTOA) of the knee is a common complication after intra- and extra-articular fractures. Moreover, PTOA may also be a result of isolated cartilage defects, meniscus resections, and ligament injuries. There are various methods of treatment of knee joint fractures. However, in the final stage of a PTOA, when nonoperative treatment fails, endoprosthetic joint replacement is the method of choice. Primary total knee replacement (TKR) for the treatment for a fracture of the knee joint is a rare indication, even at major treatment centers. It is performed in elderly patients with the inability to be mobilized with partial- or non-weight bearing; in cases with considerable bone destruction; in cases with symptomatic osteoarthritis (OA) in the elderly; and, it is often associated with the primary use of a modular implant. However, TKR in the acute situation should always be an individual decision. Secondary TKR after knee joint fracture shows overall good functional results. However, the results are inferior when compared with TKR for primary OA. In addition, the complication rates of TKR for PTOA are much higher. Problems with the extensor mechanism after tibial plateau fractures are common. There are also problems caused by preexisting scars, nonunion (possibly due to a low grade infection), malalignment, restricted movement, or instability.