The interleukin-6/gp130-associated Janus Kinases/STAT3 axis is known to play an important role in mediating inflammatory signals, resulting in production of matrix metalloproteinase-3 (MMP-3). The hip joints with rapidly destructive coxopathy (RDC) demonstrate rapid chondrolysis, probably by increased production of MMP-3 observed in the early stage of RDC. In the recent study, no apparent activation of STAT3 has been shown in the synovial tissues obtained from the osteoarthritic joint at operation. However, no data are currently available on STAT3 activation in the synovial tissues in the early stage of RDC. This study aimed to elucidate STAT3 activation in the synovial tissues in the early stage of RDC. Synovial tissues within 7 months from the disease onset were obtained from four RDC patients with femoral head destruction and high serum levels of MMP-3. RDC synovial tissues showed the synovial lining hyperplasia with an increase of CD68-positive macrophages and CD3-positive T lymphocytes. STAT3 phosphorylation was found in the synovial tissues by immunohistochemistry using anti-phospho-STAT3 antibody. The majority of phospho-STAT3-positive cells were the synovial lining cells and exhibited negative expression of macrophage or T cell marker. Treatment with tofacitinib, a Janus Kinase inhibitor, resulted in a decrease in phospho-STAT3-positive cells, especially with high intensity, indicating effective suppression of STAT3 activation in RDC synovial tissues. Inhibitory effect of tofacitinib could act through the Janus Kinase/STAT3 axis in the synovial tissues in the early stage of RDC. Therefore, STAT3 may be a potential therapeutic target for prevention of joint structural damage in RDC.

Acknowledgements: This study was supported by Katakami Foundation for Clinical Research.

Medial meniscus tear has been proposed as a potential etiology of spontaneous osteonecrosis of the knee (SONK). Disruption of collagen fibers within the meniscus causes meniscal extrusion, which results in alteration in load distribution in the knee. A recent study has demonstrated high incidence of medial meniscus extrusion in the knee with SONK. Our purpose was to determine whether the extent of medial meniscus extrusion correlates with the severity of SONK in the medial femoral condyle.

Anteroposterior and lateral knee radiographs were taken with the patients standing. Limb alignment was expressed as the femorotibial angle (FTA) obtained from the anteroposterior radiograph. The stage of progression of SONK was determined according to the radiological classification system described by Koshino. After measurement of anteroposterior, mediolateral, and superoinferior dimensions of the hypointense T1 signal intensity lesion of MRI, its ellipsoid volume was calculated with the three dimensions. Meniscal pathology (degeneration, tear, and extrusion) were also evaluated by MRI.

Of the 18 knees with SONK, we found 5 knees at the radiological stage 2 lesions, 9 knees at the stage 3, and 4 knees at the stage 4. Whereas the ellipsoid volume of SONK lesion significantly increased with the stage progression, the volume was significantly greater at stage 4 than stage 2 or 3. All the 18 knees with SONK in the present study showed substantial extrusion (> 3mm) and degeneration of the medial meniscus. While medial meniscal extrusion increased with the stage progression, medial meniscus was significantly extruded at stage 3 or 4 compared with stage 2. A significant increase in FTA was found with the stage progression. FTA was significantly greater at stage 4 than stage 2 or 3. Multiple linear regression analysis revealed that medial meniscus extrusion and FTA were useful predictors of the volume of SONK lesion.

This study has clearly shown a significant correlation between the extent of medial meniscus extrusion and the stage and volume of SONK lesion. Degeneration and tears of the medial meniscus in combination with extrusion may result in loss of hoop stress distribution in the medial compartment, which could increase the load in the medial femoral condyle. In addition to meniscal pathology, knee alignment can influence load distribution in the medial compartment biomechanically. Multiple linear regression analysis indicates that an increase in FTA concomitant with a greater extrusion of medial meniscus could result in greater lesion and advanced radiological stage of SONK. Taken together, alteration in compressive force transmission through the medial compartment by meniscus extrusion and varus alignment could develop subchondral insufficiency fractures in the medial femoral condyle, which is considered to be one of the main contributing factors to SONK development.

There was high association of medial meniscus extrusion and FTA with the radiological stage and volume of SONK lesion. Increased loading in the medial femoral condyle with greater extrusion of medial meniscus and varus alignment may contribute to expansion and secondary osteoarthritic changes of SONK lesion.