HIF-1α, an essential transcription factor under hypoxic condition, is indispensable for chondrocytes during skeletal development but its expression and roles in articular chondrocytes are yet to be revealed. We examined HIF-1α protein expression and the hypoxic condition during mouse osteoarthritis (OA) development using state of the art hypoxic probes and found that its expression decreased as OA progressed, coinciding with the change in hypoxic conditions in articular cartilage. Gain-and loss-of-function of HIF-1α in cell culture experiments showed that HIF-1α suppressed catabolic genes such as Mmp13 and Hif2a. We confirmed these anticatabolic effects by measuring glycosaminoglycan release from wild type and conditional knockout mice femoral heads cultured ex vivo. We went on to surgically induce OA in mice with chondrocyte-specific deletion of Hif1a and found that the development of OA was exacerbated. Increased expression of catabolic factors and activation of nf-κB signalling was clearly evident in the knockout mice. By microarray analysis, C1qtnf3 was identified as a downstream molecule of HIF-1α, and experiments showed it exerted anti-catabolic effects through suppression of NF-κB. We conclude that HIF-1α has an anti-catabolic function in the maintenance of articular cartilage through suppression of NF-κB signalling. Advancement in the field of musculoskeletal research has resulted in unveiling molecular mechanisms of diseases such as osteoporosis, osteoarthritis (OA) and rheumatoid arthritis (RA). These have led to inventions of evolutionary treatment and the effects have significantly decreased the number of patients requiring surgical treatment in RA. OA is a multifactorial entity caused by mechanical stress and inflammation, so to reproduce the mechanism experimentally was challenging. However, since the introduction of murine surgical knee OA models, understanding of the molecular mechanisms and signalling pathways of the disease has accelerated. Matrix metalloproteinase-13 (Mmp3), nuclear factor kappa B (NF-κB), a disintegrin-like and metallopeptidase with thrombospondin type 1 motif 5 (Adamts5) and hypoxia-inducible factor 2-alpha (HIF-2α) are the representative catabolic factors revealed to date 1-10. Among them, HIF-2α is an essential transcription factor in the pathophysiology of OA. HIF-2α is a member of HIF regulatory α-subunit proteins 11 and is actually abundantly expressed in intermediate and deep layers of osteoarthritic cartilage 8. HIF-2α is a direct transcriptional target of NF-κB, and its expression is dependent on the activation of NF-κB signalling by various stimulations 8,10. Increased HIF-2α protein further induces various catabolic factors including Mmp13, which subsequently accelerate cartilage degeneration 8 .
Osteoarthritis (OA) results from an imbalance of the dynamic equilibrium between the breakdown and repair of joint tissues. Previously, we reported that Runx1 enhanced chondrogenic differentiation through transcriptional induction of COL2A1 , and suppressed hypertrophic differentiation. Here, we investigated the involvement of Runx1 in OA development as well as its potential underlying molecular mechanism. When we analysed OA development in Col2a1-Cre;Runx1 fl/fl and Runx1 fl/fl mice by surgically inducing joint instability, Cartilage degradation and osteophyte formation of Col2a1-Cre;Runx1 fl/fl joints was accelerated compared with joints in Runx1 fl/fl animals 8 weeks after surgery. To investigate chondrocyte regulation by Runx1, we analysed interactions with co-factors and downstream molecules. Runx1 enhanced cartilage matrix production in cooperation with Sox5, Sox6, and Sox9, and co-immunoprecipitation assays showed protein–protein binding between Runx1 and each Sox protein. Knockdown of Runx1 increased expression of a hypertrophic marker, Co10a1, in mouse articular cartilage and primary chondrocytes. This expression was accompanied by decreased expression of Bapx1, a potent suppressor of hypertrophic differentiation. Notably, Runx1-induced suppression of hypertrophic differentiation was diminished by siRNA silencing of Bapx1 , whereas chondrogenic markers were unaltered. Thus, Runx1 contributes to articular cartilage maintenance by enhancing matrix production in cooperation with Sox proteins, and suppressing hypertrophic differentiation at least partly via Bapx1 induction.
Objectives: Osteosarcoma is the most common malignant bone tumor in childhood. Although a poorer prognosis has been described in older patients, few reports have focused solely on primary osteosarcoma. We evaluated the clinical features of elderly patients with primary osteosarcoma. Materials and Methods: Ninety-four patients were included in this retrospective study, and we divided them into 2 groups (older patients and younger patients) based on a cut-off age of 40 years. The patients’ information, including age, tumor type, location, presence of metastasis, American Joint Committee on Cancer (AJCC) stage, treatment-related factors, local and distant relapse, and outcome, was collected. We compared the clinical courses between the 2 groups in all and only deceased patients. Results: In all patients, the frequency of chemotherapy in the older group was significantly lower than in the younger group (p < 0.001), and tumors were more frequent in axial bone in the older patients (p = 0.041). Only in patients with surgical treatment, histological effectiveness after chemotherapy in the older group was lower than in the younger group (p = 0.041). The older patients showed a poorer prognosis (p = 0.031). However, the 5-year overall survival rate in the older patients was more favorable than that in the younger patients only among deceased patients (p =0.032). Only the existence of metastasis affected the prognosis in older patients (p = 0.012). Conclusion: Primary osteosarcoma in elderly patients showed a high incidence of axial bone involvement, a low rate of chemotherapy, and resistance to chemotherapy. Although the final life prognosis is poor, survival may be relatively prolonged.
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