Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA.

Cite this article: Bone Joint Res 2021;10(4):285–297.

Particulate wear debris can induce the release of bone-resorbing cytokines from cultured macrophages and fibroblasts in vitro, and these mediators are believed to be the cause of the periprosthetic bone resorption which leads to aseptic loosening in vivo. Much less is known about the effects of particulate debris on the growth and metabolism of osteoblastic cells. We exposed two human osteoblast-like cell lines (SaOS-2 and MG-63) to particulate cobalt, chromium and cobalt-chromium alloy at concentrations of 0, 0.01, 0.1 and 1.0 mg/ml. Cobalt was toxic to both cell lines and inhibited the production of type-I collagen, osteocalcin and alkaline phosphatase. Chromium and cobalt-chromium were well tolerated by both cell lines, producing no cytotoxicity and no inhibition of type-I collagen synthesis. At the highest concentration tested (1.0 mg/ml), however, chromium inhibited alkaline phosphatase activity, and both chromium and cobalt-chromium alloy inhibited osteocalcin expression. Our results clearly show that particulate metal debris can modulate the growth and metabolism of osteoblastic cells in vitro. Reduced osteoblastic activity at the bone-implant interface may be an important mechanism by which particulate wear debris influences the pathogenesis of aseptic loosening in vivo

1. Bones consist essentially of bundles of collagenous fibres united by a cementing substance in which the inorganic material lies in the form of minute plate-like crystals. 2. During weight bearing and muscle action bones as a whole are deformed to a variable extent. Periods of deformation are followed by periods of relaxed pressure during which the bones tend to return to their normal form. 3. These variations in deformation and elastic recoil set up alternating pressures and tensions within the bones along the bone cyrstal encrusted fibres which make up the trabeculae, lamellae and Haversian systems, and these alternating phases of compression and tension stimulate the activity of osteoblasts so that bone formation predominates over bone resorption. 4. These alterations of pressure and tension are intermittent and reciprocal in nature and do not, as postulated by the trajectorial theory, involve different trabeculae, nor is it necessary to consider whether tension or pressure is the more important phase in determining bone deposition. 5. The pressure exerted by cysts, tumours, erupting teeth, etc., is of a quite different nature, as is the response to trauma or callus formation in the healing of fractures. These processes are essentially vascular phenomena involving localised areas of bony tissue and not bones as mechanical units

A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing.

Cite this article: Bone Joint Res 2020;9(7):368–385.

Six pairs of human cadaver femora were divided equally into two groups one of which received a non-cemented reference implant and the other a very short non-dependent experimental implant. Thirteen strain-gauge rosettes were attached to the external surface of each specimen and, during application of combined axial and torsional loads to the femoral head, the strains in both groups were measured. After the insertion of a non-cemented femoral component, the normal pattern of a progressive proximal-to-distal increase in strains was similar to that in the intact femur and the strain was maximum near the tip of the prosthesis. On the medial and lateral aspects of the proximal femur, the strains were greatly reduced after implantation of both types of implant. The pattern and magnitude of the strains, however, were closer to those in the intact femur after insertion of the experimental stem than in the reference stem. On the anterior and posterior aspects of the femur, implantation of both types of stem led to increased principal strains E1, E2 and E3. This was most pronounced for the experimental stem. Our findings suggest that the experimental stem, which has a more anatomical proximal fit without having a distal stem and cortex contact, can provide immediate postoperative stability. Pure proximal loading by the experimental stem in the metaphysis, reduction of excessive bending stiffness of the stem by tapering and the absence of contact between the stem and the distal cortex may reduce stress shielding, bone resorption and thigh pain

1. When cortisone is administered to rabbits there is early rapid resorption of bone and a partial inhibition of new bone formation. After a few days the effect becomes less obvious, so that, if observations are made at later stages, the results may be ascribed then to simple inhibition of bone growth. 2. The effect of mechanical stress has been studied in the jaw. When tooth movement is induced mechanically there is, in ordinary circumstances, a resorption of bone on the side to which the tooth is moving (the "pressure" side) and bone formation on the opposite side (the "tension" side). After administration of cortisone there is increased resorption on the "pressure" side and there is greater resorption of connective tissues here. On the "tension" side there is resorption and inhibition of bone formation. 3. In the areas of stress, when cortisone is administered, collagen fibres are no longer in apposition, being separated by spaces presumably filled with altered ground substance; this kind of change may be responsible for many of the observed phenomena. 4. A.C.T.H. does not produce a demonstrable resorptive effect on bone or connective tissue until it has been administered for periods longer than is required for cortisone (three weeks); even then the change is not pronounced. 5. In the guinea pig there is slight delay in bone formation with large doses of both cortisone and A.C.T.H., but no significant bone resorption occurs

Aims

The Mathys Affinis Short is the most frequently used stemless total shoulder prosthesis in the UK. The purpose of this prospective cohort study is to report the survivorship, clinical, and radiological outcomes of the first independent series of the Affinis Short prosthesis.

Proponents of the biological theory of aseptic loosening have in recent years tended to concentrate on the production and distribution of particulate ultra-high-molecular-weight polyethylene (UHMWPE) debris around the potential joint space. However, mechanical loading of cemented implants with the differing elastic moduli of metal stems, polymethylmethacrylate (PMMA) cement and bone can result in relative micromotion, implying the potential for production of metal and PMMA particles from the stem-cement interface by fretting wear. In order to investigate the production and biological reactivity of debris from this interface, PMMA and metal particulate debris was produced by sliding wear of PMMA pins containing barium sulphate and zirconium dioxide against a Vaquasheened stainless steel counterface. This debris was characterised by SEM, energy-dispersive analysis by X-ray (EDAX) and image analysis, then added to cell cultures of a human monocytic cell line, U937, and stimulation of pro-osteolytic cytokines measured by ELISA. Large quantities of PMMA cement debris were generated by the sliding wear of PMMA pins against Vaquasheened stainless steel plates in the method developed for this study. Both cements stimulated the release of pro-osteolytic TNFα from the U937 monocytic cell line, in a dose-dependent fashion. There was a trend towards greater TNFα release with Palacos cement than CMW cement at the same dose. Palacos particles also caused significant release of IL-6, another pro-osteolytic cytokine, while CMW did not. The particulate cement debris produced did not stimulate the release of GM-CSF or IL1β from the U937 cells. These results may explain the cytokine pathway responsible for bone resorption caused by particulate PMMA debris. Radio-opaque additives are of value in surgical practice and clinical studies to quantify the relevance of these in vitro findings are required before the use of cement containing radio-opacifier is constrained

Aims

Local recurrence remains a challenging and common problem following curettage and joint-sparing surgery for giant cell tumour of bone (GCTB). We previously reported a 15% local recurrence rate at a median follow-up of 30 months in 20 patients with high-risk GCTB treated with neoadjuvant Denosumab. The aim of this study was to determine if this initial favourable outcome following the use of Denosumab was maintained with longer follow-up.

Aims

Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing.

Aims

The use of frozen tumour-bearing autograft combined with a vascularized fibular graft (VFG) represents a new technique for biological reconstruction of massive bone defect. We have compared the clinical outcomes between this technique and Capanna reconstruction.

Aseptic loosening is a major cause of failure of total hip arthroplasty. The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption. We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane. Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E. 2. (PGE. 2. ), as an indicator of COX-2 activity, was measured using an enzyme immunoassay. Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68. +. macrophages. The presence of calcium-independent iNOS activity and PGE. 2. production was confirmed in the homogenized interface membrane. Immunocytochemistry showed that periprosthetic CD68. +. wear-debris-laden macrophages were the most prominent cell type immunoreactive for iNOS, nitrotyrosine and COX-2. Other periprosthetic inflammatory and resident cell types were also found to immunolocalise nitrotyrosine thereby suggesting peroxynitrite-induced protein nitrosylation and cellular damage not only in NO-producing CD68. +. macrophages, but also in their neighbouring cells. These data indicate that both iNOS and COX-2 are expressed by CD68. +. macrophages in the interface membrane and peroxynitrite-induced cellular damage is evident in such tissue. If high-output NO and peroxynitrite generation were to cause macrophage cell death, this would result in the release of phagocytosed wear debris into the extracellular matrix. A detrimental cycle of events would then be established with further phagocytosis by newly-recruited inflammatory cells and subsequent NO, peroxynitrite and prostanoid synthesis. Since both NO and have been implicated in the induction and PGE. 2. maintenance of chronic inflammation with resulting loss of bone, and peroxynitrite in the pathogenesis of disease states, they may be central to the pathogenesis of aseptic loosening

Aims

Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA.

Aims

To analyze the potential role of synovial fluid peptidase activity as a measure of disease burden and predictive biomarker of progression in knee osteoarthritis (KOA).

Aims

Metaphyseal tritanium cones can be used to manage the tibial bone loss commonly encountered at revision total knee arthroplasty (rTKA). Tibial stems provide additional fixation and are generally used in combination with cones. The aim of this study was to examine the role of the stems in the overall stability of tibial implants when metaphyseal cones are used for rTKA.

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health.

Cite this article: Bone Joint Res 2020;9(10):709–718.

When large daily doses of vitamin D were administered to rats endochondral growth was inhibited and bone resorption occurred; later in the process uncalcified matrix (osteoid) like that seen in rickets formed on trabecular margins. When vitamin D was given only for a short period and then discontinued, little resorption of bone was seen during the withdrawal period and wide seams of osteoid material appeared which eventually calcified in an irregular manner. When normal endochondral growth was resumed a wide transverse band of dense bone with enclosed cartilaginous cores was left in the marrow cavity. If, after a few days, a second large dose of the vitamin was given resorption again occurred and calcification of osteoid material was accelerated, the first microscopic sign being a dense, wide, granular, deeply staining line at the junction of the bone and new osteoid. After a second withdrawal period a second layer of osteoid formed; eventually another transverse band appeared in the metaphysis. If this hypervitaminosis D cycle (+4 -12) was continued rats continued to form new bone with relatively little remodelling, so that after three such cycles bones became dense and hard. Histological study showed that little marrow cavity remained in either skull, vertebrae or epiphyses and a dense mass of bone enclosing cartilage cores filled the metaphysial part of the long bones. In addition, ankylosis ofteeth, calcification of spinal ligaments and widespread metastatic calcification were present. When hypervitaminosis D cycles (+1 -12, +1 -21) were adjusted to produce minimal resorptive changes a wide range of bone change was observed. This varied from uniform dense metaphysial bone containing abnormal cartilage matrix arranged in longitudinal striations, dense transverse bands parallel to the epiphysial cartilage, to remnants of dense trabeculae extending into the marrow cavity. Bone changes in osteopetrosis structurally closely resembled the induced bone changes in the rat. It is concluded that an important mechanism in the production of osteopetrosis is an accentuated rhythm of bone change like that shown experimentally to be produced in these animals. It is emphasised that these changes are but part of a range of bone disorders associated with abnormalities of cycles of resorption and deposition of bone, the type of change differing with the nature of the cycles

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.

Objectives

The osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) balance is of the utmost importance in fracture healing. The aim of this study was therefore to investigate the impact of nonosteogenic factors on OPG and RANKL levels.