Aims

cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect.

Osteoarthritis, the most common degenerative joint disease, significantly impairs life quality and labor capability of patients. Synovial inflammation, initiated by HMGB1 (High mobility group box 1)-induced activation of macrophage, precedes other pathological changes. As an upstream regulator of NF-κB (nuclear factor-kappa B) and MAPK (mitogen-activated protein kinase) signaling pathway, TAK1 (TGF-β activated kinase 1) participates in macrophage activation, while its function in osteoarthritis remains unveiled. This study aims to investigate the role of TAK1 in the pathogenesis of osteoarthritis via both in vitro and in vivo approaches.

We performed immunohistochemical staining for TAK1 in synovial tissue, both in osteoarthritis patients and healthy control. Besides, immunofluorescence staining for F4/80 as macrophage marker and TAK1 were conducted as well. TAK1 expression was examined in RAW264.7 macrophages stimulated by HMGB1 via qPCR (Quantitative polymerase chain reaction) and Western blotting, and the effect of TAK1 inhibitor (5z-7 oxozeaenol) on TNF-α production was evaluated by immunofluorescence staining. Further, we explored the influence of intra-articular shRNA (short hairpin RNA) targeting TAK1 on collagenase-induced osteoarthritis in mice.

Immunohistochemical staining confirmed significant elevation of TAK1 in osteoarthritic synovium, and immunofluorescence staining suggested macrophages as predominant residence of TAK1. In HMGB1-stimulated RAW264.7 macrophages, TAK1 expression was up-regulated both in mRNA and protein level. Besides, TAK1 inhibitor significantly impairs the production of TNF-α by macrophages upon HMGB1 stimulation. Moreover, intra-articular injection of lentivirus loaded with shRNA targeting TAK1 (sh-TAK1) reduced peri-articular osteophyte formation in collagenase-induced osteoarthritis in mice.

TAK1 exerts a potent role in the pathogenesis of osteoarthritis by mediating the activation of macrophages.

For patients who took joint replacement, one of the complications, aseptic joint loosening, could cause a high risk of revision surgery. Studies have shown that MSCs have the ability of homing and differentiating, and also have highly effective immune regulation and anti-inflammatory effects. However, few studies had focused on the stem cells in preventing the occurrence and development of aseptic loosening. In this research, we aimed to clarify whether human umbilical cord mesenchymal stem cells could inhibited the aseptic joint loosening caused by wear particles.

A Cranial osteolysis mice model was established on mice to examine the effect of hUC-MSCs on the Titanium particles injection area through micro-CT. The amount of stem cells injected was 2 × 10 5 cells. One week later, the mouse Cranial were obtained for micro-CT scan, and then stained with HE analysis immunohistochemical analysis of TNF-α, CD68, CCL3 and Il-1β.

All mice were free of fever and other adverse reactions, and there was no death occurred. Titanium particles caused the osteolysis at the mice cranial, while local injection of hUC-MSCs did inhibit the cranial osteolysis, with a lower BV/TV and a higher porosity. Immunohistochemical results suggested that the expression of TNF-α, CD68, CCL3 and Il-1β in the cranial in Titanium particles mice increased significantly, but was significantly reduced in mice injected with hUC-MSCs. The inhibited CD68 expression indicated that the number of macrophage was lower, which might be a result of the inhibition of CCL3.

According to the studies above, HUC-MSCs treatment of mouse cranial osteolysis model can significantly reduce osteolysis, inhibit macrophage recruitment, alleviate inflammatory response, without causing adverse reactions. It may become a promising treatment of aseptic joint loosening.

Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening.

Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival.

In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed.

Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required.

Osteoarthritis (OA), the most prevalent chronic joint disease, represents a relevant social and economic burden worldwide. Human umbilical cord mesenchymal stem cells (HUCMSCs) have been used for injection into the joint cavity to treat OA. The aim of this article is to clarify whether Huc-MSCs derived exosomes could inhibit the progression of OA and the mechanism in this process.

A rabbit OA model was established by the transection of the anterior cruciate ligament. The effects of HUCMSCs or exosomes derived from HUCMSCs on repairing articular cartilage of knee osteoarthritis was examined by micro-CT. Immunohistochemical experiments were used to confirm the expression of relevant inflammatory molecules in OA. In vitro experiments, Transwell assay was used to assess the migration of macrophages induced by TNF-a.

Results showed that a large number of macrophages migrated in arthcular cavity in OA model in vivo, while local injection of HUCMSCs and exosomes did repair the articular cartilage. Immunohistochemical results suggested that the expression of CCL2 and CD68 in the OA rabbit model increased significantly, but was significantly reduced by HUCMSCs or exosomes. Transwell assay showed that both HUCMSCs and exosomes can effectively inhibit the migration of macrophage.

In conclusion, the exosomes derived by HUCMSCs might might rescue cartilage defects in rabbit through its anti-inflammatory effects through inhibiting CCL2.

Osteoarthritis (OA) is a common age-related degenerative joint disease, affecting 7% of the global population, more than 500 million people worldwide. Exosomes from mesenchymal stem cells (MSCs) showed promise for OA treatment, but the insufficient biological targeting weakens its efficacy and might bring side effects. Here, we report the chondrocyte-targeted exosomes synthesized via click chemistry as a novel treatment for OA.

Exosomes are isolated from human umbilical cord-derived MSCs (hUC-MSCs) using multistep ultracentrifugation process, and identified by electron microscope and nanoparticle tracking analysis (NTA). Chondrocyte affinity peptide (CAP) is conjugated on the surface of exosomes using click chemistry. For tracking, nontagged exosomes and CAP-exosomes are labeled by Dil, a fluorescent dye that highlights the lipid membrane of exosomes. To verify the effects of CAP-exosomes, nontagged exosomes and CAP-exosomes are added into the culture medium of interleukin (IL)-1β-induced chondrocytes. Immunofluorescence are used to test the expression of matrix metalloproteinase (MMP)-13.

CAP-exosomes, compared with nontagged exosomes, are more easily absorbed by chondrocytes. What's more, CAP-exosomes induced lower MMP-13 expression of chondrocytes when compared with nontagged exosomes (p<0.001).

CAP-exosomes show chondrocyte-targeting and exert better protective effect than nontagged exosomes on chondrocyte extracellular matrix. Histological and in vivo validation are now being conducted.

Aims

It has been established that mechanical stimulation benefits tendon-bone (T-B) healing, and macrophage phenotype can be regulated by mechanical cues; moreover, the interaction between macrophages and mesenchymal stem cells (MSCs) plays a fundamental role in tissue repair. This study aimed to investigate the role of macrophage-mediated MSC chondrogenesis in load-induced T-B healing in depth.

Aims

To fully quantify the effect of posterior tibial slope (PTS) angles on joint kinematics and contact mechanics of intact and anterior cruciate ligament-deficient (ACLD) knees during the gait cycle.

Aims

The value of core decompression (CD) in the treatment of osteonecrosis of the femoral head (ONFH) remains controversial. We conducted a systematic review and meta-analysis to evaluate whether CD combined with other treatments could improve the clinical and radiological outcomes of ONFH patients compared with CD alone.

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated.

Cite this article: Bone Joint Res 2020;9(8):524–530.

Aims

The aim of this study was to explore the prognostic factors for postoperative neurological recovery and survival in patients with complete paralysis due to neoplastic epidural spinal cord compression.

Background

Revision total ankle arthroplasty (TAA) can be extremely challenging due to bone loss and deformity. We present the results examining the preliminary indications and short term outcomes for the use of the Salto XT revision prosthesis.

Background

Subtalar nonunion has a detrimental effect on patients' function, and pose a significant challenge for surgeons particularly in the setting of higher risk factors.

Müller Weiss disease (MWD) is characterized by lateral navicular necrosis which is associated with a varus alignment of the subtalar joint, varying degrees of arthritis of the talonavicular-cuneiform joints and a paradoxical flatfoot deformity in advanced cases. Although arthrodesis of the hindfoot is commonly used, we present the results of a previously unreported method of treatment using a calcaneus osteotomy incorporating a wedge and lateral translation.

Fourteen patients with MWD who were treated with a calcaneus osteotomy were retrospectively reviewed. There were seven females and seven males with an average age of 56 years (range 33–79), and included one grade 5, five grade 4, four grade 3 and four grade 2 patients. Patients had been symptomatic for an average of eleven years (range 1–14), and all underwent initial conservative treatment with an orthotic support that posted the heel into valgus. The primary indication for surgery was a limited but positive response to the use of the orthotic support, and a desire to avoid an arthrodesis of the hindfoot.

Background

There have been multiple techniques described to determine hindfoot alignment radiographically. The 2-dimensional nature of radiographs fails to take into account the contribution of the remainder of the foot to overall alignment. A new radiographic technique has been published in which the hindfoot alignment is calculated using the Ground Reaction Force Calcanea Offset. This technique accounts for the individual forefoot contribution to alignment, but is still limited by it´s 2-dimensional nature. The purpose of this study was to compare the hindfoot moment arm (HMA) described by Saltzman and the hindfoot alignment angle (HAA) described by Williamson, with a technique determining the ground reaction force calcaneal offset (GRF-CT) using 3-dimensional weight bearing CT Scans.

Introduction

Novel chondroitin sulphate (CS) sulphation motifs on cell-associated proteoglycans (PGs) have been shown to be putative biomarkers of progenitor/stem cell sub-populations (Hayes et al., 2007; Dowthwaite et al., 2005). Also, recent studies show that unique CS sulphation motifs are localized in putative stem/progenitor cell niches at sites of incipient articular cartilage & other musculoskeletal tissues (Hayes et al., 2011), which indicates their potential importance in cell differentiation during development. In this study, we investigated the importance of CS in the differentiation of bone marrow stem cells to the chondrogenic phenotype in vitro using p-nitrophenyl xyloside (PNPX) as a competitive inhibitor of CS substitution on matrix PGs.

Introduction

Kashin-Beck disease (KBD) is an endemic degenerative osteoarthropathy affecting approximately 3 million people in China (Stone R, 2009). The precise aetiology of KBD is not clear, but the lack of selenium and the pollution of mycotoxins in food are a suspected cause of KBD. In this pilot study, we use a rat model to investigate the effect of low selenium and T-2 toxin on articular cartilage metabolism.

Introduction

Low back pain is a major public health problem in our society. Degeneration of intervertebral disc (IVD) appears to be the leading cause of chronic low-back pain [1]. Mechanical stimulations including compressive and tensional forces are directly implicated in IVD degeneration. Several studies have implicated the cytoskeleton in mechanotransduction [2, 3], which is important for communication and transport between the cells and extracellular matrix (ECM). However, the potential roles of the cytoskeletal elements in the mechanotransduction pathways in IVD are largely unknown.

Introduction: In a previous study (Hayes et al., 2007)we reported that novel chondroitin sulphate (CS) sulphation motifs on cell-associated proteoglycans (PGs) may be putative biomarkers of progenitor/stem cell sub-populations resident within the superficial zone of articular cartilage (Dowthwaite et al., 2005). In this study, using the same panel of antibodies, we examine the distribution of novel CS sulphation epitopes in a more clinically relevant model – the developing human knee joint.

Methods: Twelve-14 week human foetal knee joint rudiments were processed into paraffin wax then de-waxed and immunoperoxidase-stained with mAbs 3B3(−), 7D4 and 4C3 using the Vector Universal Elite kit with Nova Red, Mayers Haematoxylin, mounted under coverslips and then photographed.

Results: All three CS sulphation motif epitopes localised prominently at sites of incipient articular cartilage formation at a stage before there was any histological evidence of secondary ossification at the epiphysis. Interestingly, these CS epitopes were also detectable in very defined regions within the perichondrium; growth plate; the fibrocartilage of both meniscus and enthesis; vasculature; and at sites of capillary invasion, with subtle differences in their distribution; for example, 3B3(−) identified the cellular lining of cartilage canals within the epiphyses, whereas 7D4 labelled more their cellular contents.

Discussion: The results of this study show that novel CS sulphation motifs on cell and matrix PGs play important and diverse roles in the development of a wide range of musculoskeletal connective tissues, including articular cartilage. We hypothesize that the unique sulphation sequences on CS-containing PGs are involved in regulating cell proliferation and differentiation events, through interaction with soluble signalling molecules (e.g. growth factors) in the extracellular milieu. These antibodies show considerable promise for uses in tissue engineering applications for identifying and sorting stem/progenitor cells for regeneration of musculoskeletal tissues.

Introduction: Kashin-Beck disease (KBD) is a special endemic osteoarthropathy whose main pathologic changes occur in growth plate cartilage and articular cartilage of human limbs and joints where it is manifested as cartilage degeneration and necrosis. Past and current research suggests that KBD, and its endemic geographic distribution in China, is due to the combined presence of fungal mycotoxins (on stored food ingested by affected populations) and a regional selenium deficiency in the environment providing local food sources. Thus, we hypothesise that the presence of fungal mycotoxins and the absence of selenium in the diet specifically affects chondrocyte metabolism in the growth plate during limb and joint development and in articular cartilage of adults, which leads to localised tissue necrosis, and the onset of degenerative joint disease. The aim of this study was to examine the effects of mycotoxins; e.g. Nivalenol (NIV), selenium and NIV in the presence of selen! ium in in vitro chondrocyte culture systems to better understand cellular and molecular mechanisms underlying the pathogenesis of KBD.

Methods: Chondrocyte tissue cultures were established using cartilage explant cultures either in the presence or absence of selenium (0.5–1.5 microg/ml) and the mycotoxin nivalenol (0.5–1.5 microg/ml) and culture for 1 to 4 days. Medium was harvested daily at day 1 through 4 and analysed for glycosaminoglycan (GAG) release and the presence of aggrecanase or MMP activity using RT-PCR for gene expression and monoclonal antibodies that detect their respective enzyme-generated neo-epitopes on cartilage aggrecan metabolites.

Results: Our studies to date have shown that NIV exposure induces catabolic changes in chondrocyte metabolism with an increased expression of aggrecanase activity. Addition of selenium did not affect mRNA expression of the aggrecanases ADAMTS-4 & 5. Parallel studies involving immunohistochemical analyses of articular cartilage from KBD showed an increase in aggrecanase activity.

Conclusions: These studies demonstrate that induction of aggrecanase activity as one of the molecular mechanisms involved is the pathogenesis of KBD. However, the addition of selenium does not alter aggrecanase gene expression indicating that its beneficial effects are occurring in other areas of cartilage metabolism.

Introduction: Kashin-Beck disease (KBD) is an endemic osteoarthropathy with pathological changes occurring in growth plate and articular cartilage in humans. It manifests as cartilage degeneration and necrosis. It is postulated that KBD is due to fungal mycotoxins infiltrating the diet and a regional selenium deficiency in the environment providing food sources in a broad belt across China. Previous work has established an in vitro system in which chondrocytes are cultured and an ex vivo cartilage graft is produced. Subjecting these chondrocytes to either selenium (SEL), Nivalenol (NIV) or in combination during the growth of the graft was found to alter the morphology of the cartilage graft. In addition, the quantity of the large aggregating proteoglycan, was significantly reduced in a dose dependent manner in the presence of Nivalenol. This study aimed to examine the composition of aggrecan from grafts grown in the presence of NIV or SEL alone, or in combination to better understand cellular and molecular mechanisms underlying the pathogenesis of KBD.

Methods: Chondrocytes (from 7 day old bovine cartilage) were seeded at high density in MilliCell filter inserts (12mm diameter; Millipore, MA). Cultures were maintained for 4 weeks in DMEM supplemented with 20% heat–inactivated FBS, ascorbate (100μg/ml) and TGFß2 (5ng/ml) or additionally supplemented with either SEL , NIV or both at concentrations of 0.01, 0.05 and 0.1μg/ml. Media was refreshed thrice weekly and later analysed. At 4 weeks the cartilage grafts were harvested, weighed and extracted in 4M guanidium chloride (with an inhibitor cocktail) for biochemical analysis of matrix molecules. Residues were papain digested. Glycosaminoglycan concentration was determined using the DMMB assay in all media samples, guanidine extracts and papain digests. Aggrecan and GAG composition was determined using Western blotting with a panel of antibodies recognising chondroitin sulphate (CS), keratan sulphate (KS) and protein core epitopes present in aggrecan.

Results: The total GAG synthesised in a 4week period was substantially reduced in chondrocytes cultured in the presence of NIV at 0.05 and 0.1μg/ml and to a lesser extent in those cultures exposed to the highest dose of SEL. However, the amount of GAG released into the media remained fairly constant within the treatment groups, but a marked reduction was apparent in the guanidine extracts of the cartilage grafts. Western blot analysis with a series of antibodies on guanidine extracted aggrecan showed no substantial changes in the core protein molecular weights however analysis demonstrated that KS was reduced in NIV treated cultures. Results also indicated that NIV treated cultures appeared to contain less CS substitutions on the aggrecan core protein.

Discussion: The GAG concentration data indicates that there is an inability of the GAG to remain within the cartilage grafts extracellular matrix. when treated with NIV. Western blot analysis indicates minor changes in the composition of the aggrecan in relation to protein core length and CS/KS side chain substitutions or length. Further work will investigate the proportion of aggrecan able to form high molecular weight aggregates, the metabolism of link protein and hyaluronan.

Radiodense structures resembling ossicles at the acetabular rim have received multiple names including “Os acetabuli, Os supertilii, Os marginale superius acetabuli, and Os coxae quartum”.

Various theories regarding their origin have been postulated. These structures commonly are observed in dysplastic hips and hips suffering from femoro-acetabular impingement and represent fractures of the acetabular rim. In our series we observed acetabular rim fragments in 4.9% of the dysplastic hips and in 6.4% of the hips with femoro-acetabular impingement.

Two different pathomechanics are responsible for the occurrence of these rim fragments. In dysplasia the short acetabular roof reduces the amount of available loading surface which leads to an overload on the lateral margin of the acetabulum, propagating the development of a fatigue fracture. However, as in all hips additional cysts were visible, it must be postulated, that cysts have to be present additionally and act as stress risers through which the rim bone eventually will fail. In hips with femoro-acetabular impingement the mode of failure is different. The relative anterior overcover in retroverted hips is subjected to stress during flexion of the hip, which is further increased by the frequent presence of an non-spheric extension of the femoral head as seen in cam impingement. The nonspheric femoral head-neck junction is jammed into the rim area. By repetitive traumatization the anterior rim eventually will fracture.

The clinical importance of acetabular rim fractures in the dysplastic hip is readily understood even by an unexperienced observer. However, it has to be considered as a sign that the hip has decompensated and it usually goes with significant articular cartilage damage. Because the radiographic appearance of the hip with femoro-acetabular impingement seems normal at first sight, the mechanism leading to anterior rim fracture may be overlooked. However, recognition and adequate treatment is important to prevent further degeneration of the hip.

Directly molding IB, MG and AGC UHMWPE tibial inserts has provided excellent clinical performance. This performance may be related to the oxidation resistance and higher fracture toughness provided by the direct molding process. Directly molded UHMWPE components have been reported not to oxidize after either nine years post irradiation aging on the shelf or after 11 years of implantation. Retrievals show that molded IB inserts to have lower oxidation, better polyethylene quality and less surface damage than machined IB II inserts. However, the IB, MG and AGC products were directly molded from 1900 UHMWPE resin which is no longer available. The question remains if directly molding resins other than 1900 in a contemporary modular design will provide the same benefits. We report here on the first knee simulation wear of a contemporary total knee system comprised of a directly molded 1020 esin tibial insert. This result will be compared to the knee simulation result of an IBII machined from 4150 extruded ro 4 Optetrak tibial inserts made by directly molding 1020 resin were tested on a 4 station Instron/Stanmore simulator at 1.4 Hz with a 2279 N maximum load and right knee kinematics. The lubricant was bovine calf serum with EDTA and sodium azide. Axial loads were applied from 0 to 40& #778; flexion and internal/external rotation was −3/+6 degrees. Location, type and area of surface damage, were evaluated every 1 million cycles (Mc).

The wear rate of the directly molded inserts was 6X less than reported for machined IB II inserts (2 vs 12 mg/million cycles respectively). There were no signs of delamination or pitting with either design. The more conforming Optetrak provided 52% reduction in wear area over the IB II (21 vs 32 % respectively). This demonstrates that resins other than 1900 may be directly molded in a contemporary and provide the same historical advantages.

It is estimated that there will be over 12,000 total shoulder replacements implanted this year. In the best series, the survivorships of these devices are 90% at 7 years. However, there are radiographic indications that the long term success will be limited to wear and damage to the polyethylene glenoid components. Like tibial insert in total knee replacements, the glenoid is subjected to both rolling sliding motions of a metal counterface. Additionally, the compressive loads on the glenoid have been estimated to be as high as 2800N under ‘normal’ conditions. In contrast to tibial inserts, glenoid components are all typically less than 6 mm thick. In metal backed glenoid devices, the polyethylene thickness is often < 3 mm. The effect of these parameters and kinematics on polyethylene damage has not previously described. Although total shoulder replacements have been in use for over 25 years, there have been no reports describing the nature and extent of glenoid polyethylene wear and damage.

We report the determination of polyethylene damage type and severity of 38 retrieved glenoid components of at least 4 different designs. Wear and damage were considered significant when either 80% of the glenoid surface was damaged or if over 25% of the component was worn away. Abrasion, burnishing and pitting were the main modes of damage. There were 2 fractured components. There was significant UHMWPE wear and damage in 17 (45%) components. In nine of these, the component was completely worn through.. These findings are consistent with high stress, high wear conditions and thin polyethylene components.

These results indicate polyethylene wear and damage is expected to be a key factor in limiting the survivor-ship total shoulder replacements and that polyethylene damage and wear in total shoulder replacements may be higher than that found for either total hip or knee replacements.