Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a pivotal role in this physioxic environment. In normoxic conditions, HIFs are downregulated, whereas in physioxic conditions, they are upregulated. The HIF-α family comprises three members: HIF-1α, HIF-2α, and HIF-3α. Each member has a distinct function in articular cartilage. In osteoarthritis, which is primarily caused by degeneration of articular cartilage, HIF-1α is upregulated in chondrocytes and is believed to protect articular cartilage by acting anabolically on it. Conversely, in contrast to HIF-1α, HIF-2α exerts a catabolic influence on articular cartilage. It may therefore be possible to develop a new treatment for OA by controlling the expression of HIF-1α and HIF-2α with drugs or by altering the oxygen environment in the joints.

Background/Objectives: Medial open wedge high tibial osteotomy (MOWHTO) has led to favorable clinical results since the introduction of locking plates. Surgical indications, techniques, and postoperative alignment are crucial for achieving favorable clinical outcomes. This study analyzed the clinical outcomes of patients after >5 years of post-MOWHTO follow-up to identify the influential factors. Methods: Thirty-nine patients (48 knees) underwent MOWHTO for medial compartment knee osteoarthritis or -necrosis and were followed up for >5 years. The targeted postoperative % mechanical axis (%MA) was 62.5% (Fujisawa point). The Japanese Orthopaedic Association (JOA) Knee Disease Outcome Criteria score; Kellgren–Lawrence classification; hip-knee-ankle, medial proximal tibial, mechanical lateral distal femoral, and joint line convergence angles (JLCA); and %MA were evaluated preoperatively, at implant removal, and at the final follow-up. Total knee arthroplasty (TKA) was the survival endpoint. Uni- and multivariate analyses were performed to identify the factors influencing survival rates. Results: The mean JOA score improved from preoperative to implant removal and was sustained at 102 months. Four of the 48 knees required TKA, resulting in a 10-year survival rate of 82%. Body mass index, preoperative JLCA, and Δ%MA influenced the post-MOWHTO survival rate. The Δ%MA was significantly greater in the group with a %MA < 62.5% at implant removal. Conclusions: MOWHTO with a target %MA of 62.5% yielded favorable long-term outcomes. Additionally, preoperative obesity and high joint instability negatively influenced post-MOWHTO survival. Furthermore, a postoperative %MA of < 62.5% is associated with difficulty maintaining stable alignment and an increased risk of conversion to TKA.

Bone marrow stimulation is a treatment for articular cartilage injuries that promotes cartilage repair by inducing the migration and accumulation of mesenchymal stem cells (MSCs), but often results in fibrocartilage with limited durability. This study aimed to investigate the effect of hypoxic conditions on cartilage repair using a rat osteochondral defect model. Osteochondral defects (1.0 mm in diameter) were created in the femoral trochlear groove, and rats were exposed to hypoxic conditions (12% O₂) for 4 weeks postoperatively. Histological analysis was performed, and protein expression of hypoxia-inducible factor-1α (HIF-1α) and SRY-box transcription factor 9 (SOX9) in the repair tissue was evaluated after 1 week. As a result, after 1 week, protein expression of HIF-1α and SOX9 in the Hypoxia group was significantly increased compared to the Normoxia group. After 4 weeks, the Hypoxia group exhibited a hyaline cartilage-like tissue structure with a significantly lower Modified Wakitani score compared to the Normoxia group. Furthermore, after 4 weeks, the inhibition of HIF-1α suppressed cartilage repair. These findings suggest that hypoxic conditions promote SOX9 expression via HIF-1α during the early phase of MSC chondrogenic differentiation and promote the formation of hyaline cartilage-like repair tissue. In conclusion, bone marrow stimulation under hypoxic conditions may enhance the repair effect on articular cartilage injuries.

Background/Objectives: After open-wedge high tibial osteotomy (OWHTO), the patella is displaced distally, causing patellofemoral joint degeneration. The objective of this study was to ascertain whether the combination of OWHTO and lateral retinacular release (LRR) can prevent articular cartilage degeneration of the patellofemoral joint using magnetic resonance imaging T2 mapping. Methods: This study included 37 patients (37 knees) who underwent OWHTO alone (OWHTO group) and 37 patients (37 knees) who underwent OWHTO with LRR (OWHTO + LRR group) with a correction angle of <10° for varus knee osteoarthritis. MRI was performed on all knees prior to and 6 months after surgery to assess the patellar cartilage in sagittal images for T2 mapping. Three regions of interest, (the medial facet, patellar ridge, and lateral facet), were established for the articular cartilage on the patellar side. The T2 values were subsequently quantified. Lower limb alignment, patellar height, patellar tilt angle, and lateral shift ratio were evaluated pre-and post-surgery. Results: Mean T2 values at 6 months post-surgery of the medial facet and patellar ridge of the OWHTO group showed a significant increase after surgery; no significant changes were observed in either region in the OWHTO + LRR group. In both groups, a significant decrease in patellar tilt angle was observed postoperatively; no change was noted in the lateral shift ratio or congruence angle. The change in patellar tilt angle was significantly lower in the OWHTO + LRR group than in the OWHTO group. Conclusions: LRR combined with OWHTO prevented patellofemoral joint cartilage degeneration after surgery in cases of varus knee osteoarthritis.

We investigated the effects of belt electrode-skeletal muscle electrical stimulation (B-SES) on muscle atrophy in collagen-induced arthritis (CIA) rats. Twenty-eight 8-week-old male Dark Agouti rats were immunized with type II collagen and Freund’s incomplete adjuvant (day 0). From days 14 to 28, 18 rats received B-SES (50 Hz) four times only on the right hindlimb (STIM), while the contralateral left hindlimb remained unstimulated. Both hindlimbs of 10 untreated CIA rats were defined as controls (CONT). Paw volume was measured every other day. On day 28, the muscle weight, histology, and gene expression of the soleus and extensor digitorum longus (EDL) were analyzed. B-SES did not worsen paw volume throughout the experimental period. Compared with CONT, the muscle weight and fiber cross-sectional area of the soleus were higher in STIM. The expression of muscle degradation markers (atrogin-1 and MuRF-1) in the soleus and EDL was lower in the STIM group than that in the CONT group. In contrast, B-SES did not significantly affect the expression of muscle synthesis (Eif4e and p70S6K) and mitochondrial (PGC-1α) markers. B-SES prevents muscle atrophy in CIA rats by reducing muscle degradation without exacerbating arthritis, demonstrating its promising potential as an intervention for RA-induced muscle atrophy.

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA.