Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature.

BACKGROUND: Knee Osteoarthritis (KOA) is a heterogeneous pathology characterized by a complex and multifactorial nature. It has been hypothesised that these differences are due to the existence of underlying phenotypes representing different mechanisms of the disease. METHODS: The aim of this study is to identify the current evidence for the existence of groups of variables which point towards the existence of distinct clinical phenotypes in the KOA population. A systematic literature search in PubMed was conducted. Only original articles were selected if they aimed to identify phenotypes of patients aged 18 years or older with KOA. The methodological quality of the studies was independently assessed by two reviewers and qualitative synthesis of the evidence was performed. Strong evidence for existence of specific phenotypes was considered present if the phenotype was supported by at least two high-quality studies. RESULTS: A total of 24 studies were included. Through qualitative synthesis of evidence, six main sets of variables proposing the existence of six phenotypes were identified: 1) chronic pain in which central mechanisms (e.g. central sensitisation) are prominent; 2) inflammatory (high levels of inflammatory biomarkers); 3) metabolic syndrome (high prevalence of obesity, diabetes and other metabolic disturbances); 4) Bone and cartilage metabolism (alteration in local tissue metabolism); 5) mechanical overload characterised primarily by varus malalignment and medial compartment disease; and 6) minimal joint disease characterised as minor clinical symptoms with slow progression over time. CONCLUSIONS: This study identified six distinct groups of variables which should be explored in attempts to better define clinical phenotypes in the KOA population.

[Dynamics of changes in bone mineral density and structural organization in cosmonauts following space flight of 6 months in duration].

Microgravity effect on bone tissue of cosmonauts was evaluated following space flights of 6 months in duration. Peripheral quantitative computed tomography (pQCT) was used to determine volumetric bone mineral density (VBMD) and structure of distal parts of the leg and forearm. Changes in VBMD were found to correlate with bone position relative to the vector of gravity. In the forearm, reversible hypermineralization was bound together with compact bone thickening. Reversible osteopenia in the lower leg was accompanied with plausible losses both in compact and trabecular bone. Irrespective of position relative to the vector of gravity, bone microarchitecture tended to reduce the number of trabecules and to increase heterogeneity of the trabecular network. Pre-flight structural dynamics showed a complex character with linear time dependence.

Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength.

Osteoclasts are unique cells that utilize podosomes instead of focal adhesions for matrix attachment and cytoskeletal remodeling during motility. We have shown that osteopontin (OP) binding to the alpha(v)beta(3) integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp(60c-src), and phosphatidylinositol 3'-kinase. Here we demonstrate that gelsolin deficiency blocks podosome assembly and alpha(v)beta(3)-stimulated signaling related to motility in gelsolin-null mice. Gelsolin-deficient osteoclasts were hypomotile due to retarded remodeling of the actin cytoskeleton. They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption. Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth. However, gelsolin-null mice had mildly abnormal epiphyseal structure, retained cartilage proteoglycans in metaphyseal trabeculae, and increased trabecular thickness. With age, the gelsolin-deficient mice expressed increased trabecular and cortical bone thickness producing mechanically stronger bones. These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin.

Relationships between legs bone mineral density, anthropometry and jumping height in prepubertal children.

The aim of this study was to determine how the legs bone mineral density (BMD) is influenced by anthropometry and vertical jumping height in prepubertal children. In total, 64 8-11-year-old schoolchildren (27 boys and 37 girls) were studied. All children were at Tanner stage 1. The subjects' height and body mass were measured and BMI calculated. The following anthropometric parameters directly connected with leg were measured: skinfolds--front thigh and medial calf girths--gluteal, thigh, mid-thigh, calf and ankle; lengths--iliospinale height, trochanterion height, trochanteriontibiale laterale, tibiale-laterale height and tibiale mediale-spyrion tibiale; and breadths--biiliocristal, foot length and biepicondylar femur. Total body and legs fat mass and fat %, lean body mass (LBM) and both legs BMD were measured by DXA. Maximal jumping height was measured on the contact mat. Stepwise multiple regression analysis indicated that body height in boys (54.6%; R2 x 100) and body mass in girls (57.3%) were the most important basic anthropometric parameters that influenced BMD in legs. From the measured skinfolds, that of the front thigh characterized legs BMD by 24.9-35.6%. From the girths, the most important parameter to characterize legs BMD was that of calf (50.0-59.1%). Tibiale laterale height was the only length parameter which was highly related with legs BMD (51.1-54.5%). Biepicondylar femur was the most important breadth parameter which characterized legs BMD (51.0-54.8%). Femur breadth and tibiale-laterale height were selected (68.7%) in boys, and tibiale-laterale height and front thigh skinfold thickness (66.0%) in girls when all measured leg anthropometric parameters were analyzed together. From the body composition parameters, the most important parameter to characterize legs BMD was legs LBM (48.9-59.5%). Jumping height did not correlate with legs BMD in any studied groups. In summary, the present study demonstrated that legs LBM together with tibiale-laterale height are the main predictors of legs BMD in prepubertal children.

Lectin and other histochemical studies of the articular cartilage and the chondro-osseous junction of the normal human knee joint.

There are few studies on normal, adult diarthrodial joints which look in detail at the histochemical properties of the chondro-osseous junctional region. This study of the normal human knee joint was performed using lectin and other histochemical techniques. There were differences in the reactions of mineralised cartilage compared to those of hyaline cartilage with the former demonstrating more collagen and less glycosaminoglycans. Lectin histochemistry revealed more accessible terminal 2-deoxy,2-acetamido-alpha-D: -galactose and more N-acetyllactosamine but less fucosyl and alpha-2,6-linked-sialyl termini in the mineralised cartilage. The hyaline cartilage chondrocytes stained for N-glycans but those of mineralised cartilage did not. The staining patterns of prolongations and islands of uncalcified cartilage running through the calcified layer to abut bone and marrow spaces were distinct, resembling the patterns of the hyaline cartilage but with some unique features. A possible relationship was revealed between the presence of the Maclura pomifera ligand (Galbeta1,3GalNAcalpha1-) and mineralisation. Subchondral bone had a markedly restricted glycoprofile.

Mechanical loading modulates glutamate receptor subunit expression in bone.

The cellular mechanisms coupling mechanical loading with bone remodeling remain unclear. In the CNS, the excitatory amino acid glutamate (Glu) serves as a potent neurotransmitter exerting its effects via various membrane Glu receptors (GluR). Nerves containing Glu exist close to bone cells expressing functional GluRs. Demonstration of a mechanically sensitive glutamate/aspartate transporter protein and the ability of glutamate to stimulate bone resorption in vitro suggest a role for glutamate linking mechanical load and bone remodeling. We used immunohistochemical techniques to identify the expression of N-methyl-d-aspartate acid (NMDA) and non-NMDA (AMPA or kainate) ionotropic GluR subunits on bone cells in vivo. In bone sections from young adult rats, osteoclasts expressed numerous GluR subunits including AMPA (GluR2/3 and GluR4), kainic acid (GluR567) and NMDA (NMDAR2A, NMDAR2B and NMDAR2C) receptor subtypes. Bone lining cells demonstrated immunoexpression for NMDAR2A, NMDAR2B, NMDAR2C, GluR567, GluR23, GluR2 and GluR4 subunits. Immunoexpression was not evident on osteocytes, chondrocytes or vascular channels. To investigate the effects of mechanical loading on GluR expression, we used a Materials Testing System (MTS) to apply 10 N sinusoidal axial compressive loads percutaneously to the right limbs (radius/ulna, tibia/fibula) of rats. Each limb underwent 300-load cycles/day (cycle rate, 1 Hz) for 4 consecutive days. Contralateral, non-loaded limbs served as controls. Mechanically loaded limbs revealed a load-induced loss of immunoexpression for GluR2/3, GluR4, GluR567 and NMDAR2A on osteoclasts and NMDAR2A, NMDAR2B, GluR2/3 and GluR4 on bone lining cells. Both neonatal rabbit and rat osteoclasts were cultured on bone slices to investigate the effect of the NMDA receptor antagonist, MK801, and the AMPA/kainic acid receptor antagonist, NBQX, on osteoclast resorptive activity in vitro. The inhibition of resorptive function seen suggested that both NMDAR and kainic acid receptor function are required for normal osteoclast function. While the exact role of ionotropic GluRs in skeletal tissue remains unclear, the modulation of GluR subunit expression by mechanical loading lends further support for participation of Glu as a mechanical loading effector. These ionotropic receptors appear to be functionally relevant to normal osteoclast resorptive activity.

[Effect of opiod peptides on free radical oxidation in a bone regenerate after fracture].

Opioid peptides (DSLET and DAGO) stimulating bone tissue regeneration were studied for effects on content of free radical products in regenerate tissue from the region of leg fracture in mice at various terms of reparative osteogenesis. These opioids reduce concentration of malonic dialdehyde and dienic conjugastes in bone for 10 days after fracture.

γ-Irradiation sterilized bone strengthened and toughened by ribose pre-treatment.

OBJECTIVE: This study tested the hypothesis that a ribose-based pre-treatment would protect the strength, ductility and toughness of γ-irradiation sterilized cortical bone. METHODS: Experiment 1: The effects of ribose pre-treatment (1.8M in PBS at 60°C for 24h) prior to 33 kGy of irradiation on strength, ductility and toughness (beams in three-point bending) and fracture toughness (J-integral at instability in single edge notched (bending)) were tested against matched non-irradiated and irradiated controls from bovine tibiae. Experiment 2: Three-point bending tests were conducted using beams from human femora (males, 59-67 years). Bone collagen thermal stability and network connectivity were examined using hydrothermal isometric tension testing. RESULTS: Ribose pre-treatment protected the strength, ductility and toughness of irradiation sterilized bovine and human specimens to differing degrees. Their ultimate strength was not detectably different from non-irradiated control levels; toughness in bovine and human specimens was protected by 57 and 76%, respectively. Untreated human bone was less affected by irradiation and ribose pre-treatment was more effective in human bone than bovine bone. CONCLUSIONS: This paper presents the first proof-of-principle that irradiation-sterilized bone with improved mechanical properties can be produced through the application of a ribose pre-irradiation treatment, which provides a more stable and connected collagen network than found in conventionally irradiated controls.

Identification of promoter regions involved in cell- and developmental stage-specific osteopontin expression in bone, kidney, placenta, and mammary gland: an analysis of transgenic mice.

UNLABELLED: Cell-specific expression of GFP under the control of different lengths of the osteopontin promoter in transgenic mice identified the positive and negative regulatory regions for respective cell types. The results provide new insights for physiological and pathological expression of the osteopontin gene. INTRODUCTION: Osteopontin (OPN) is a major non-collagenous bone matrix protein that is involved in normal and pathological calcification and is expressed in a tissue-specific manner. To investigate how such tissue-specific OPN gene expression is regulated in vivo, transgenic mice expressing the green fluorescent protein (GFP) reporter gene controlled by different lengths of the OPN promoter were generated. MATERIALS AND METHODS: Cell- and developmental stage-specific osteopontin expression in transgenic mice was examined by Northern blotting, immunoblotting, fluorescence examination, and in situ hybridization and compared with those of OPN. RESULTS AND CONCLUSIONS: The line bearing the -5505 to +14 region of the OPN promoter was shown by Northern blotting and immunoblotting to express GFP in the same cells that express endogenous OPN (osteoblasts, hypertrophic chondrocytes, renal and mammary gland epithelial cells, and granulated metrial gland [GMG] placental cells) at the same stage in development. Thus, the 5.5-kb -5505 to +14 promoter region is sufficient for proper tissue-specific OPN expression. The lines carrying shorter segments of the OPN promoter showed different expression patterns. These patterns revealed a putative cis-acting element in the -5269 to -5263 region that restricts OPN expression to hypertrophic chondrocytes and a mammary gland-specific expressing element and a GMG cell-specific enhancing element in the -5505 to -3156 region. Furthermore, the -3155 to -1576 region seems to contain positive renal epithelial cell- and GMG cell-specific expression motif(s) as well as a negative regulatory element that prevents OPN expression in fibroblasts. Moreover, the -1576 to -910 region seems to contain a positive osteoblast-specific-expressing element. Thus, the 5.5-kb OPN promoter contains multiple cis-acting elements encoding positive and negative cell-specific regulatory systems.

Intense 201 Tl uptake in giant-cell tumour of bone.

The aim of this study was to determine the characteristics and clinical usefulness of 201Tl scintigraphy in giant-cell tumour of bone (GCT). Twenty-one patients with histopathologically proven benign GCT (22 lesions; 18 primary and four recurrent) underwent 201Tl scintigraphy. We also studied conventional osteosarcoma (10 lesions), a very common primary malignant bone tumour; and chordoma in the sacrum (four lesions), an entity requiring differential diagnosis from GCT of the sacrum. Early and delayed planar imaging was performed at 15 min (early) and 3 h (delayed) after the intravenous injection of 201Tl chloride (111 MBq). The Tl uptake ratio was calculated by dividing the count density of the tumour region of interest (ROI) by that of the background ROI. All GCT lesions showed increased Tl uptake in both early and delayed images. The mean Tl uptake ratios of primary GCT were 4.7 (range, 2.0-11.1) in the early images and 2.2 (range, 1.4-3.6) in the delayed images, and those of recurrent lesions were 5.8 (range, 2.4-11.5) in the early images and 2.7 (range, 2.0-4.3) in the delayed images. There were no significant differences between the uptake ratios in GCT and osteosarcoma, but the values of GCT tended to be higher than those of osteosarcoma, 3.1 (range, 1.7-4.4) in the early images and 1.8 (range, 1.3-2.3) in the delayed images. Chordoma did not show appreciable Tl uptake: the uptake ratio was 1.19 (range, 0.98-1.5) in the early images and 1.1 (range, 1.0-1.3) in the delayed images. In GCT, a benign lesion, Tl scintigraphy demonstrated marked uptake in both primary and recurrent lesions with no exceptions, precluding the use of Tl scintigraphy for the differential diagnosis of GCT from malignant tumours. However, the Tl scintigraphy can be used for excluding GCT when no lesional Tl uptake is observed, and diagnosing recurrent lesions on post-operative follow-up.

Tc-99m sestamibi bone marrow scintigraphy in Gaucher disease.

PURPOSE: No imaging technique has been found to be adequate to assess the severity and extent of bone involvement in patients with Gaucher disease. Marrow involvement, as determined by Tc-99m sulfur colloid, correlated well with the clinical and radiologic changes of the skeleton, but a normal pattern was found in the early stages of the disease. Subsequently, Tc-99m sestamibi (MIBI) has been suggested for direct visualization of glycolipid deposits in the bone marrow. This study was initiated as a pilot using MIBI to detect various forms of bone disease in patients with Gaucher disease of varying severity. MATERIALS AND METHODS: Eleven patients (9 men; median age, 39.9; age range, 21 to 61 years) were evaluated. The clinical severity of disease was scored at presentation, and four patients with moderate to severe disease were treated with enzyme replacement therapy. Each patient underwent a radiographic skeletal survey, bone densitometry, and MIBI scintigraphy. The scan included static images of the lower limbs, with a whole-body scan acquired between the early and late acquisition. Tracer uptake in the bone marrow was graded and correlated with clinical and objective variables. RESULTS: All but one patient had increased MIBI uptake in the bone marrow. No correlation was noted between MIBI uptake and severity score, radiographic changes, densitometry z score, or treatment status. CONCLUSIONS: MIBI scanning is a sensitive technique for detecting bone marrow deposits in Gaucher disease, but it is inadequate for early identification of patients at high risk for skeletal complications or for the follow-up of patients treated with enzyme replacement.

[La accumulation and microstructure change of leg bones of rats fed with La(NO(3))(3) in low dosage for a long term].

OBJECTIVE: To study La accumulation and microstructure change of leg bones of rats fed with La(NO(3))(3) in low dosage for a long term. METHODS: After the rats were fed by La(NO(3))(3) in dosage of 2 mg x (kg(-1) x d(-1)) for 6 months, the contents of La and Ca,P in the leg bones were determined by ICP MS and spectrophotometry; the microstructure changes of the leg bones were investigated by electron microscopy and X-ray powder diffraction. RESULTS: In the leg bones of tested rats, the contents of La and P increased greatly, and those of Ca did not change obviously, so that Ca/P ratio values decreased in comparison with the control group. CONCLUSION: La was accumulatied in the rat leg bones and the change of bone microstructure induced after the rats were fed with La(NO(3))(3) in low dosage for a long term.

Preventive effects of the methanol soluble fraction of Millettia macrophylla Benth (Fabaceae) on an osteoporosis-like model of ovariectomized Wistar rats.

BACKGROUND: Millettia macrophylla Benth is a Cameroonian medicinal plant traditionally used to alleviate menopause-related problems. The methanol soluble fraction of this plant was shown to exhibit estrogenic effects in vitro in Human Embryonic kidney cells, and in vivo on ovariectomized rat following the classical uterotrophic assay. Since estrogens have been involved in bone remodeling process, the present study then aimed at evaluating bone loss preventive effects of the methanol soluble fraction of Millettia macrophylla (MM-met) in ovariectomized rat model. METHODS: Twenty-five healthy Wistar female rats (3-month-old) were randomly assigned to a sham-operated group and to four treated ovariectomized (OVX) groups. Treatments lasted 8 weeks and animals were sacrificed. The uterus, the femoral and the tibia bones of each animal were collected, weighed and fixed in 10% formalin for histological analysis. RESULTS: Results showed that ovariectomy decreased uterine wet weight (p<0.01), induced body weight gain (p<0.01), decreased both femoral and tibia bone density and mineral content and increased alkaline phosphatase activity (p<0.05). E2V and MM-met treatments in general prevented bone mass loss and/or bone density loss. At all tested doses, MM-met induced a significant decrease of alkaline phosphatase activity (p<0.05). As observed with E2V, MM-met also induced a significant protective effect on bone, and this was indicated by an abundance of bone marrow in an almost intact trabecular network. CONCLUSIONS: The overall results show that the methanol soluble fraction of Millettia macrophylla may prevent ovariectomy-induced bone mass loss and deterioration of the trabecular microarchitecture.

Bone lead levels and lead isotope ratios in red grouse from Scottish and Yorkshire moors.

Leg and foot bones of adult and juvenile red grouse (Lagopus lagopus scoticus) were collected from hunter-shot birds on two Scottish estates (Glendye and Invermark) and one Yorkshire estate in September, 2003. The lead content of bones was measured by atomic absorption spectrophotometry, and corresponding stable lead isotopes (Pb(204, 206, 207, 208)) by inductively coupled plasma mass spectrometry. At the Glendye (N=111) and Invermark (N=85) estates, relatively few birds (5.4% and 3.5%, respectively) had highly elevated bone lead concentrations (>20 microg/g dry weight). In bones of these highly exposed birds, a combination of Pb(206):Pb(207) and Pb(208):Pb(207)ratios was consistent with ingestion of lead gunshot available in Europe. By contrast, Yorkshire grouse experienced a high incidence (65.8%) of bone lead >20 microg/g. The Pb(206):Pb(207) and Pb(208):Pb(207)ratios in bones of these highly exposed birds were consistent with a combined exposure to ingested lead gunshot and lead from galena mining in the region. Lead isotope ratios also indicated that lead from UK gasoline combustion and fallout from atmospheric particles was not a likely source of elevated lead in bones of either Scottish or Yorkshire grouse. Suggested management options for the three moors include adopting nontoxic shot for all game shooting on the estates, allowing heather (Calluna vulgaris) vegetation to grow tall in lead shot fall-out zones to reduce physical access to high densities of lead shot already present, and provision of calcareous grit across moors to reduce lead assimilation from all ingested sources of lead.

Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty.

OBJECTIVES: To investigate plasma and bone moxifloxacin concentrations following oral administration of a single or double dose of the drug, in order to consider its potential role in the treatment of osteomyelitis. PATIENTS AND METHODS: Thirty consecutive patients undergoing total knee arthroplasty were recruited. Three groups, of ten patients each, were formed: group A received moxifloxacin 400 mg orally 2 h (range 1.5-2.5) preoperatively, group B received moxifloxacin 400 mg orally 4 h (range 3.5-4.5) preoperatively and group C received moxifloxacin 400 mg orally 14 h preoperatively, followed by a second dose 2 h (range 1.5-2.5) preoperatively. During surgery, at the time of bone removal, a blood sample and aliquots of cortical and cancellous bone were collected and moxifloxacin concentrations were measured by HPLC. RESULTS: Mean plasma, cancellous bone and cortical bone concentrations were, respectively: 3.45, 1.89 and 1.43 mg/L for group A; 3.73, 1.81 and 1.56 mg/L for group B; and 6.26, 2.97 and 2.54 mg/L for group C. CONCLUSIONS: These data show a good penetration of moxifloxacin into both cancellous and cortical bone, with concentrations, after double dosing, exceeding the MIC90 for most pathogens involved in osteomyelitis and the clinic susceptibility breakpoint for Mycobacterium tuberculosis.

Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity.

Most current models propose Sonic hedgehog (Shh) as the primary determinant of anteroposterior development of amniote limbs. Shh protein is said to be required to direct the formation of skeletal elements and to specify digit identity through dose-dependent activation of target gene expression. However, the identity of genes targeted by Shh, and the regulatory mechanisms controlling their expression, remain poorly understood. Gli3 (the gene implicated in human Greig cephalopolysyndactyly syndrome) is proposed to negatively regulate Shh by restricting its expression and influence to the posterior mesoderm. Here we report genetic analyses in mice showing that Shh and Gli3 are dispensable for formation of limb skeletal elements: Shh(-/-) Gli3(-/-) limbs are distally complete and polydactylous, but completely lack wild-type digit identities. We show that the effects of Shh signalling on skeletal patterning and ridge maintenance are necessarily mediated through Gli3. We propose that the function of Shh and Gli3 in limb skeletal patterning is limited to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification, by regulating the relative balance of Gli3 transcriptional activator and repressor activities.