Exposure of articular cartilage to excessive mechanical loading is deeply involved in the pathogenesis of osteoarthritis. Here, we identify gremlin-1 as a mechanical loading-inducible factor in chondrocytes, detected at high levels in middle and deep layers of cartilage after cyclic strain or hydrostatic pressure loading. Gremlin-1 activates nuclear factor-κB signalling, leading to subsequent induction of catabolic enzymes. In mice intra-articular administration of gremlin-1 antibody or chondrocyte-specific deletion of Gremlin-1 decelerates osteoarthritis development, while intra-articular administration of recombinant gremlin-1 exacerbates this process. Furthermore, ras-related C3 botulinum toxin substrate 1 activation induced by mechanical loading enhances reactive oxygen species (ROS) production. Amongst ROS-activating transcription factors, RelA/p65 induces Gremlin-1 transcription, which antagonizes induction of anabolic genes such as Sox9 , Col2a1 , and Acan by bone morphogenetic proteins. Thus, gremlin-1 plays essential roles in cartilage degeneration by excessive mechanical loading.

BackgroundBoth loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage.MethodsWnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-CreERT2;Ctnnb1fl/fl and Prg4-CreERT2;Ctnnb1-ex3fl/wt mice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells.ResultsWnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4.ConclusionsWe demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.

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 .

OBJECTIVEPreoperative mood disorders such as depression and anxiety are known to be associated with poor health-related quality of life (HRQOL) outcomes after lumbar spine surgery. However, the effects of preoperative depression and anxiety on postoperative HRQOL outcomes and patient satisfaction in cervical compressive myelopathy are yet to be clarified. This study aimed to investigate the effect of depression and anxiety on HRQOL outcomes and patient satisfaction following surgery for cervical compressive myelopathy.METHODSThe authors reviewed the cases of all consecutive patients with cervical compressive myelopathy who had undergone surgical treatment in the period between January 2012 and March 2017 at their institution. Using the Hospital Anxiety and Depression Scale (HADS), the authors classified patients as depressed (HADS-D+) or not depressed (HADS-D−) and anxious (HADS-A+) or not anxious (HADS-A−). Patient HRQOL was evaluated preoperatively and at the end of at least 1 year after surgery using the physical and mental component summaries of the SF-12 Health Survey, EQ-5D (EuroQol health survey of five dimensions), Neck Disability Index, and Japanese Orthopaedic Association scale. Patient satisfaction was evaluated on the basis of a seven-item questionnaire and divided into two categories: satisfied and dissatisfied. Preoperative HRQOL statuses, postoperative improvements in HRQOL outcomes, and patient satisfaction were compared between the groups.RESULTSAmong the 121 patients eligible for inclusion in the study, there were 69 patients (57.0%) without depression (HADS-D−) and 52 (43.0%) with depression (HADS-D+) and 82 patients (67.8%) without anxiety (HADS-A−) and 39 (32.2%) with anxiety (HADS-A+). All patients who completed both the preoperative and postoperative questionnaires had significant postoperative improvements in all HRQOL outcomes. The HADS-D+ and HADS-A+ patients had poorer preoperative HRQOL statuses than the HADS-D− and HADS-A− patients, respectively. However, statistically significant improvements in all HRQOL outcomes were observed in both HADS-D+ and HADS-A+ patients. Patient satisfaction was comparable between the HADS-D or HADS-A groups.CONCLUSIONSCervical compressive myelopathy patients with preoperative depression or anxiety according to the HADS tool had worse preoperative HRQOL statuses. However, patients with cervical compressive myelopathy showed significant improvements in HRQOL outcomes and had sufficient levels of satisfaction after surgery regardless of the presence of preoperative depression or anxiety.

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