Healthy limb joints are important for maintaining health and attaining longevity. Endochondral ossification (the replacement of cartilage with bone, occurring during skeletal development) is essential for bone formation, especially in long-axis bones. In contrast to endochondral ossification, chondrocyte populations in articular cartilage persist and maintain joint tissue into adulthood. Articular cartilage, a connective tissue consisting of chondrocytes and their surrounding extracellular matrices, plays an essential role in the mechanical cushioning of joints in postnatal locomotion. Osteoarthritis (OA) pathology relates to disruptions in the balance between anabolic and catabolic signals, that is, the loss of chondrocyte homeostasis due to aging or overuse of cartilages. The onset of OA increases with age, shortening a person’s healthy life expectancy. Although many people with OA experience pain, the mainstay of treatment is symptomatic therapy, and no fundamental treatment has yet been established. To establish regenerative or preventative therapies for cartilage diseases, further understanding of the mechanisms of cartilage development, morphosis, and homeostasis is required. In this review, we describe the general development of cartilage and OA pathology, followed by a discussion on anabolic and catabolic signals in cartilage homeostasis, mainly microRNAs.

We analyzed the influence of treadmill running on rheumatoid arthritis (RA) joints using a collagen-induced arthritis (CIA) rat model. Eight-week-old male Dark Agouti rats were randomly divided into four groups: The control group, treadmill group (30 min/day for 4 weeks from 10-weeks-old), CIA group (induced CIA at 8-weeks-old), and CIA + treadmill group. Destruction of the ankle joint was evaluated by histological analyses. Morphological changes of subchondral bone were analyzed by μ-CT. CIA treatment-induced synovial membrane invasion, articular cartilage destruction, and bone erosion. Treadmill running improved these changes. The synovial membrane in CIA rats produced a large amount of tumor necrosis factor-α and Connexin 43; production was significantly suppressed by treadmill running. On μ-CT of the talus, bone volume fraction (BV/TV) was significantly decreased in the CIA group. Marrow star volume (MSV), an index of bone loss, was significantly increased. These changes were significantly improved by treadmill running. Bone destruction in the talus was significantly increased with CIA and was suppressed by treadmill running. On tartrate-resistant acid phosphate and alkaline phosphatase (TRAP/ALP) staining, the number of osteoclasts around the pannus was decreased by treadmill running. These findings indicate that treadmill running in CIA rats inhibited synovial hyperplasia and joint destruction.

We investigated the effects of hypoxia-inducible factor (HIF)-1α on articular cartilage under mechanical stimulation and the associated mechanisms. Chondrocytes, isolated from articular cartilage from the knee, hip, and shoulder joints of Wistar rats, were subjected to 20 % tensile stress under hypoxic (5% O2) conditions for 24 h. HIF-1α and aggrecan expression was significantly enhanced with mechanical stimulation under hypoxia but not significantly altered with mechanical stimulation under normoxia. The nuclear translocation of HIF-1α was enhanced by mechanical stress under hypoxia. Under both normoxia and hypoxia, a disintegrin and metalloproteinase with thrombospondin motifs (ADAM-TS) 5 expression was significantly reduced with mechanical stimulation compared to that in the group without mechanical stimulation. However, HIF-1α knockdown mitigated changes in aggrecan and ADAM-TS5 expression mediated by mechanical stimulation under hypoxia. The effects of treadmill running on HIF-1α production in the articular cartilage of rat knee joints were also analyzed. HIF-1α production increased in the moderate running group and decreased to the same levels as those in the control group in the excessive running group. This suggests that HIF-1α regulates aggrecan and ADAM-TS5 expression in response to mechanical stimulation under hypoxia and general mechanical stimulation in articular cartilage under hypoxia, while controlling cartilage homeostasis.

Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.

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.

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.