Large Lytic Defects Produce Kinematic Instability and Loss of Compressive Strength in Human Spines: An in Vitro Study.

BACKGROUND: In patients with spinal metastases, kinematic instability is postulated to be a predictor of pathologic vertebral fractures. However, the relationship between this kinematic instability and the loss of spinal strength remains unknown. METHODS: Twenty-four 3-level thoracic and lumbar segments from 8 cadaver spines from female donors aged 47 to 69 years were kinematically assessed in axial compression (180 N) and axial compression with a flexion or extension moment (7.5 Nm). Two patterns of lytic defects were mechanically simulated: (1) a vertebral body defect, corresponding to Taneichi model C (n = 13); and (2) the model-C defect plus destruction of the ipsilateral pedicle and facet joint, corresponding to Taneichi model E (n = 11). The kinematic response was retested, and compression strength was measured. Two-way repeated-measures analysis of variance was used to test the effect of each model on the kinematic response of the segment. Multivariable linear regression was used to test the association between the kinematic parameters and compressive strength of the segment. RESULTS: Under a flexion moment, and for both models C and E, the lesioned spines exhibited greater flexion range of motion (ROM) and axial translation than the control spines. Both models C and E caused lower extension ROM and greater axial, sagittal, and transverse translation under an extension moment compared with the control spines. Two-way repeated-measures analysis revealed that model E, compared with model C, caused significantly greater changes in extension and torsional ROM under an extension moment, and greater sagittal translation under a flexion moment. For both models C and E, greater differences in flexion ROM and sagittal translation under a flexion moment, and greater differences in extension ROM and in axial and transverse translation under an extension moment, were associated with lower compressive strength of the lesioned spines. CONCLUSIONS: Critical spinal lytic defects result in kinematic abnormalities and lower the compressive strength of the spine. CLINICAL RELEVANCE: This experimental study demonstrates that lytic foci degrade the kinematic stability and compressive strength of the spine. Understanding the mechanisms for this degradation will help to guide treatment decisions that address inferred instability and fracture risk in patients with metastatic spinal disease.

Biomechanical Properties of Metastatically Involved Osteolytic Bone.

PURPOSE OF REVIEW: Skeletal metastasis involves the uncoupling of physiologic bone remodeling resulting in abnormal bone turnover and radical changes in bony architecture, density, and quality. Bone strength assessment and fracture risk prediction are critical in clinical treatment decision-making. This review focuses on bone tissue and structural mechanisms altered by osteolytic metastasis and the resulting changes to its material and mechanical behavior. RECENT FINDINGS: Both organic and mineral phases of bone tissue are altered by osteolytic metastatic disease, with diminished bone quality evident at multiple length-scales. The mechanical performance of bone with osteolytic lesions is influenced by a combination of tissue-level and structural changes. This review considers the effects of osteolytic metastasis on bone biomechanics demonstrating its negative impact at tissue and structural levels. Future studies need to assess the cumulative impact of cancer treatments on metastatically involved bone quality, and its utility in directing multimodal treatment planning.

BMP2 signalling activation enhances bone metastases of non-small cell lung cancer.

Distant metastases occur when non-small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre-osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre-osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling.

Proximal-medial part in the coracoid graft demonstrates the most evident stress shielding following the Latarjet procedure: a simulation study using the 3-dimensional finite element method.

BACKGROUND: Although the osteolysis of the coracoid graft is frequently observed after the Latarjet procedure particularly in its proximal part, its pathomechanism is not well understood. METHODS: Three-dimensional finite element glenohumeral joint models were developed using CT-DICOM data of 10 normal shoulders. A 25% bony defect was created on the anterior glenoid rim, and the coracoid process was transferred flush with the glenoid cartilage using 2 half-threaded screws. In the hanging arm as well as in the 90° abducted positions, a compressive load (50 N) was applied to the greater tuberosity toward the center of the glenoid and a tensile force (20 N) was applied to the coracoid tip along the direction of the conjoint tendon. Next, elastic analysis was performed, and the distribution patterns of the equivalent stress as well as the maximum principal stress were compared among 4 parts (proximal/distal and medial/lateral) of the coracoid graft. RESULTS: Both the equivalent stress and the maximum principal stress were reduced in the proximal half of the coracoid graft. A high stress concentration was observed in the lateral aspect of the coracoid graft particularly in the 90° abducted position. The proximal-medial part demonstrated the lowest equivalent stress as well as the maximum principal stress for both arm positions, which were significantly lower than those in the distal 2 parts. CONCLUSION: In the Latarjet procedure, the proximal-medial part of the coracoid graft demonstrated the most evident stress shielding, which may play an important role in postoperative osteolysis.

Reduction of SOST gene promotes bone formation through the Wnt/ß-catenin signalling pathway and compensates particle-induced osteolysis.

The increase in bone resorption and/or the inhibition of bone regeneration caused by wear particles are the main causes of periprosthetic osteolysis. The SOST gene and Sclerostin, a protein synthesized by the SOST gene, are the characteristic marker of osteocytes and regulate bone formation and resorption. We aimed to verify whether the SOST gene was involved in osteolysis induced by titanium (Ti) particles and to investigate the effects of SOST reduction on osteolysis. The results showed osteolysis on the skull surface with an increase of sclerostin levels after treated with Ti particles. Similarly, sclerostin expression in MLO-Y4 osteocytes increased when treated with Ti particles in vitro. After reduction of SOST, local bone mineral density and bone volume increased, while number of lytic pores on the skull surface decreased and the erodibility of the skull surface was compensated. Histological analyses revealed that SOST reduction increased significantly alkaline phosphatase- (ALP) and osterix-positive expression on the skull surface which promoted bone formation. ALP activity and mineralization of MC3T3-E1 cells also increased in vitro when SOST was silenced, even if treated with Ti particles. In addition, Ti particles decreased ß-catenin expression with an increase in sclerostin levels, in vivo and in vitro. Inversely, reduction of SOST expression increased ß-catenin expression. In summary, our results suggested that reduction of SOST gene can activate the Wnt/ß-catenin signalling pathway, promoting bone formation and compensated for bone loss induced by Ti particles. Thus, this study provided new perspectives in understanding the mechanisms of periprosthetic osteolysis.

Minimally Invasive Image-Guided Ablation, Osteoplasty, Reinforcement, and Internal Fixation (AORIF) for Osteolytic Lesions in the Pelvis and Periarticular Regions of Weight-Bearing Bones.

PURPOSE: To assess early outcome, safety, and complications of an alternative to open surgical treatments of osteolytic lesions in periarticular load-bearing bones. MATERIALS AND METHODS: A single-center, prospective clinical cohort study of 26 lesions in 23 consecutive patients with painful osteolytic skeletal lesions was performed. Patients were followed for an average of 7 mo (1-18 mo). Lesions were targeted from the most intact bone via minimally invasive percutaneous approach for stable anchorage of internal fixation screws using fluoroscopic guidance. Cannulated screws served as universal portals for ablation, balloon osteoplasty, and delivery of bone cement in addition to internal fixation for cement anchoring and prophylactic stabilization of uninvolved bone. RESULTS: There were 19 osteolytic lesions in the pelvis, 4 in the proximal femur, 2 in the proximal tibia, and 1 in the calcaneus. All defects were associated with severe pain or fractures. There were no conversions to open surgery and no infection or bleeding requiring transfusion, embolization, or additional procedures. There was significant improvement in visual analogue scale (VAS) pain score from 8.32 ± 1.70 to 2.36 ± 2.23, combined pain and functional ambulation score from 4.48 ± 2.84 to 7.28 ± 2.76, and Musculoskeletal Tumor Society score from 45% to 68% (P < .05). CONCLUSIONS: Ablation, osteoplasty, reinforcement, and internal fixation is a safe and effective minimally invasive percutaneous image-guided treatment option for functional improvement or palliation of painful osteolytic lesions in the pelvis and periarticular loadbearing bones.

KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone.

We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.

The 2018 Otto Aufranc Award: How Does Genome-wide Variation Affect Osteolysis Risk After THA?

BACKGROUND: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown. QUESTIONS/PURPOSES: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis. METHODS: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken. RESULTS: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10). CONCLUSIONS: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease. CLINICAL RELEVANCE: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.

Risk analysis of patients with an osteolytic acetabular defect after total hip arthroplasty using subject-specific finite-element modelling.

AIMS: Osteolysis, secondary to local and systemic physiological effects, is a major challenge in total hip arthroplasty (THA). While osteolytic defects are commonly observed in long-term follow-up, how such lesions alter the distribution of stress is unclear. The aim of this study was to quantitatively describe the biomechanical implication of such lesions by performing subject-specific finite-element (FE) analysis on patients with osteolysis after THA. PATIENTS AND METHODS: A total of 22 hemipelvis FE models were constructed in order to assess the transfer of load in 11 patients with osteolysis around the acetabular component of a THA during slow walking and a fall onto the side. There were nine men and two women. Their mean age was 69 years (55 to 81) at final follow-up. Changes in peak stress values and loads to fracture in the presence of the osteolytic defects were measured. RESULTS: The von Mises stresses were increased in models of those with and those without defects for both loading scenarios. Although some regions showed increases in stress values of up to 100%, there was only a moderate 11.2% increase in von Mises stress in the series as a whole. The site of fracture changed in some models with lowering of the load to fracture by 500 N. The most common site of fracture was the pubic ramus. This was more frequent in models with larger defects. CONCLUSION: We conclude that cancellous defects cause increases in stress within cortical structures. However, these are likely to lead to a modest decrease in the load to fracture if the defect is large (> 20cm3) or if the patient is small with thin cortical structures and low bone mineral density. Cite this article: Bone Joint J 2018;100-B:1455-62.

Physiological and pathological osteocytic osteolysis.

Osteocytes, the most abundant bone cell in the adult skeleton, can function as mechanosensors directing osteoblast and osteoclast function in order to maintain optimal load bearing bone in addition to functioning as endocrine cells regulating phosphate metabolism. A controversial function, previously overlooked or denied, has been osteocytes as regulators of calcium metabolism. Early histologists upon observing enlarged osteocyte lacunae in bone sections proposed that mature osteocytes could remove their perilacunar matrix, a term called "osteocytic osteolysis". New insights into this process have occurred during the last decade using novel technology thereby providing a means to identify molecular mechanisms responsible for osteocytic osteolysis. As release of calcium from a mineralized matrix requires a more acidic pH and specialized enzymes, it was proposed that osteocytes may utilize similar molecular mechanisms as osteoclasts to remove mineral. The idea that a cell descended from mesenchymal progenitors (the osteocyte) could function similarly to a cell descended from hematopoietic progenitors (the osteoclast) was challenged as being improbable. Here we review the molecular mechanisms behind this osteocyte function, the role of osteocytic osteolysis in health and disease, and the capacity of the osteocyte to reverse the osteolytic process by replacing the removed matrix, a revived osteoblast function.

Association of high titers of anti-carbamylated protein antibodies with decreased bone mineral density in early arthritis patients.

Rheumatoid arthritis (RA) has a negative impact on bone that is partly mediated by anti-citrullinated proteins antibodies (ACPA). These antibodies are associated with erosions, and with juxta-articular and systemic bone loss. Other RA autoantibodies, the anti-carbamylated protein antibodies (anti-CarPA), are independently associated with erosions. However, we do not know if they are also associated with juxta-articular and systemic bone loss. Here, we have addressed this question with data from 548 early arthritis (EA) patients. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry at the lumbar spine (LS), total hip (TH) and metacarpophalangeal joints (MCP). The 25.9% anti-CarPA positive patients did not show significant differences in BMD Z-scores with the negative patients. Nevertheless, this result was due to the similarity between negative and low-positive (below the median of the positive) patients, whereas the high-positive patients showed significant decrease of BMD at LS (ß = -0.39, p = 0.01) and TH (ß = -0.30, p = 0.02); but not at the juxta-articular bone of MCP. Given the overlap between anti-CarPA and ACPA, we included the two autoantibodies in an analysis that showed significantly lower BMD Z-scores at LS and TH (p< 0.01) only in the ACPA positive/anti-CarPA high-positive subgroup. However, the similar coefficients of regression between the ACPA positive/anti-CarPA high-positive and the ACPA negative/anti-CarPA high-positive subgroups (ß = -0.50 vs. -0.52 at LS, and ß = -0.37 vs. -0.30 at TH) suggested an independent association. Overall, these results support a contribution of anti-CarPA to systemic bone loss in EA patients.

Resolving Macrophages Counter Osteolysis by Anabolic Actions on Bone Cells.

Progression of inflammatory osteolytic diseases, including rheumatoid arthritis and periodontitis, is characterized by increased production of proinflammatory mediators and matrix-degrading enzymes by macrophages and increased osteoclastic activity. Phenotypic changes in macrophages are central to the healing process in virtually all tissues. Using a murine model of periodontitis, we assessed the timing of macrophage phenotypic changes and the impact of proresolving activation during inflammatory osteolysis and healing. Proinflammatory macrophage activation and TNF-α overproduction within 3 wk after induction of periodontitis was associated with progressing bone loss. Proresolving activation within 1 wk of stimulus removal and markers of resolving macrophages (IL-10, TGF-ß, and CD206) correlated strongly with bone levels. In vivo macrophage depletion with clodronate liposomes prevented bone resorption but impaired regeneration. Induction of resolving macrophages with rosiglitazone, a PPAR-γ agonist, led to reduced bone resorption during inflammatory stimulation and increased bone formation during healing. In vitro assessment of primary bone marrow-derived macrophages activated with either IFN-γ and LPS (proinflammatory activation) or IL-4 (proresolving activation) showed that IL-4-activated cells have enhanced resolving functions (production of anti-inflammatory cytokines; migration and phagocytosis of aged neutrophils) and exert direct anabolic actions on bone cells. Cystatin C secreted by resolving but not inflammatory macrophages explained, in part, the macrophage actions on osteoblasts and osteoclasts. This study supports the concept that therapeutic induction of proresolving functions in macrophages can recouple bone resorption and formation in inflammatory osteolytic diseases.

Female Human Spines with Simulated Osteolytic Defects: CT-based Structural Analysis of Vertebral Body Strength.

Purpose To evaluate a CT structural analysis protocol (SAP) for estimating the strength of human female cadaveric spines with lytic lesions. Materials and Methods Osteolytic foci was created in the middle vertebra of 44 thoracic and lumbar three-level segments from 11 female cadavers (age range, 50-70 years). The segments underwent CT by using standard clinical protocol and their failure strength was assessed at CT SAP. The spines were mechanically tested to failure in pure axial compression or in compression with torsion. The relationships of defect size, bone mineral density, and predicted failure load (at CT SAP) with measured vertebral strength were assessed with linear regression. Analysis of variance and Tukey test were used to evaluate the effect of region and mechanical test on spine strength. Results With axial compression, CT SAP predictions of vertebral strength correlated with the thoracic (r = 0.84; P < .001) and lumbar (r = 0.85; P < .001) segment-measured strength. Bone mineral density correlated with the lumbar (r = 0.64; P = .003) and thoracic (r, 0.51; P = .050) strength. At compression with torsion, CT SAP predictions of strength were moderately correlated with vertebral strength (r = 0.66; P = .018). At compression with torsion, bone mineral density was not correlated with spinal strength (thoracic and lumbar: r = 0.31 and r = 0.26, respectively; P = .539 and .610, respectively). The lytic focus size (range, 28%-41%) was not associated with vertebral strength. Conclusion CT SAP assessment of strength in vertebrae with lytic lesions correlated with the measured strength of female vertebral bodies. © RSNA, 2018 Online supplemental material is available for this article.

Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype.

Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14's transport to the cell membrane. Instead, it partially impairs MMP14's proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14's catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.

LncRNA DANCR involved osteolysis after total hip arthroplasty by regulating FOXO1 expression to inhibit osteoblast differentiation.

BACKGROUND: Aseptic loosening of artificial hip joint is a major complication affecting the long-term use of the artificial hip joint, and is the main cause of joint replacement failure. However, the mechanism of aseptic loosening of THR has not yet cleared. The aim of this study was to investigate the underlying mechanism of DANCR in osteoblast differentiation (OD). METHODS: We detected the expressions of DANCR and FOXO1 in clinical samples and mesenchymal stem cells (MSCs) by qRT-PCR and western blotting. The effects of polymethylmethacrylate (PMMA) on OD of MSCs were examined by alkaline phosphatase (ALP) activity and Alizarin Red S (ARS) staining. The expressions of OD markers were measured by qRT-PCR and western blotting. The mechanism of DANCR in OD was detected by RNA pull-down, RNA immunoprecipitation (RIP) assay and ubiquitination assays. RESULTS: Compared with the surrounding normal tissues, DANCR expression was up-regulated and FOXO1 expression was down-regulated in periprosthetic tissues. PMMA suppressed ALP activity, increased DANCR expression, and decreased the expressions of FOXO1, Runx2, Osterix (Ostx) and osteocalcin (OCN). ARS staining showed that PMMA inhibited the OD of MSCs. Knockdown of DANCR attenuated the inhibitory effect of PMMA on OD. Knockdown of FOXO1 could reverse the effect of si-DANC. RNA pull-down and RIP assay implicated that DANCR bound to FOXO1. Ubiquitination assay indicated that si-DANCR could repress Skp2-mediated ubiquitination of FOXO1. CONCLUSION: LncRNA DANCR could inhibit OD by regulating FOXO1 expression.

Fate of coracoid grafts after the Latarjet procedure: will be analogous to the original glenoid by remodelling.

PURPOSE: To evaluate the location, magnitude, and change over time of osteolysis of coracoid grafts after Latarjet procedure. METHODS: This is a retrospective study of 54 patients (55 shoulders) who underwent the Latarjet procedure. Three-dimensional computed tomography (CT) scans were performed preoperatively, immediately postoperatively, and at follow-up (mean 7.7 and 31.7 months postoperative). "En face" views of the glenoid, size of glenoid defect and changes in the glenoid surface area postoperatively were measured relative to the area of an assumed outer-fitting circle. On the oblique sagittal planes, location and subsequent severity of osteolysis of the graft at follow-up were documented. RESULTS: The mean glenoid surface area increased significantly from 79.7 ± 4.8% of the original circle preoperatively to 111.3 ± 8.0% immediately postoperatively. At 7.7 and 31.7 months of follow-up, glenoid surface area decreased to 102.2 ± 6.0% and 100.3 ± 5.3%, respectively. Osteolysis occurred on the outer side of the graft in all cases, but did not occur on the inner side. Maximum osteolysis was observed in the superior third of the graft (78.5 ± 17.1%), followed by the middle third (15.8 ± 10.4%), and the inferior third (8.0 ± 5.1%). No significant difference in magnitude of osteolysis was observed between 7.7 and 31.7 months of follow-up. CONCLUSION: Osteolysis of the grafted coracoid mainly occurred on the outer side of the superior portion, resulting in reshaping of the rectangular shape of graft coracoids after Latarjet procedure. Coracoid graft remodelling was almost completed approximately 8 months postoperatively to reach the original glenoid dish with no further changes thereafter. These results may help surgeons to understand changes of grafts after the surgery. LEVEL OF EVIDENCE: IV.

Art, the visual imagination and neuroscience: The Chauvet Cave, Mona Lisa's smile and Michelangelo's terribilitá.

This paper considers several types of imagination relevant to art historical enquiry. These are exemplified in artistic expressions ranging from palaeolithic paintings in the Chauvet Cave, to drawings, sculptures and buildings designed by Michelangelo and drawings and paintings by Leonardo, and are related to recent neuroscientific discoveries. From this it emerges that important types of imagination cannot be understood without an appreciation of the neural processes that underlie them and especially without an acknowledgement of the importance of neurochemistry.

Mechanisms of bone destruction in multiple myeloma.

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of an increased activity of osteoclasts, which is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition. Among them, the most important include the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the macrophage inflammatory proteins and the activin-A that play a crucial role in osteoclast stimulation in myeloma, while the wingless-type (Wnt) signalling inhibitors (sclerostin and dickkopf-1) along with the growth factor independence-1 are considered the most important factors for the osteoblast dysfunction of myeloma patients. Finally, the role of osteocytes, which is the key cell for normal bone remodelling, has also revealed during the last years through their interaction with myeloma cells that leads to their apoptosis and the release of RANKL and sclerostin maintaining bone loss in these patients. This review focuses on the latest available data for the mechanisms of bone destruction in multiple myeloma.

Immobilization-induced osteolysis and recovery in neuropathic foot impairments.

BACKGROUND: Neuropathic foot impairments treated with immobilization and off-loading result in osteolysis. In order to prescribe and optimize rehabilitation programs after immobilization we need to understand the magnitude of pedal osteolysis after immobilization and the time course for recovery. OBJECTIVE: To determine differences in a) foot skin temperature; b) calcaneal bone mineral density (BMD) after immobilization; c) calcaneal BMD after 33-53weeks of recovery; and d) percent of feet classified as osteopenic or osteoporotic after recovery in participants with neuropathic plantar ulcers (NPU) compared to Charcot neuroarthropathy (CNA). METHODS: Fifty-five participants with peripheral neuropathy were studied. Twenty-eight participants had NPU and 27 participants had CNA. Bilateral foot skin temperature was assessed before immobilization and bilateral calcaneal BMD was assessed before immobilization, after immobilization and after recovery using quantitative ultrasonometry. RESULTS: Before immobilization, skin temperature differences in CNA between their index and contralateral foot were markedly higher than NPU feet (3.0 degree C versus 0.7 degree C, respectively, p<0.01); BMD in NPU immobilized feet averaged 486±136mg/cm2, and CNA immobilized feet averaged 456±138mg/cm2, p>0.05). After immobilization, index NPU feet lost 27mg/cm2; CNA feet lost 47mg/cm2 of BMD, p<0.05. After recovery, 61% of NPU index feet and 84% of CNA index feet were classified as osteopenic or osteoporotic. CONCLUSIONS: There was a greater osteolysis after immobilization with an attenuated recovery in CNA feet compared to NPU feet. The attenuated recovery of pedal BMD in CNA feet resulted in a greater percentage of feet classified as osteoporotic and osteopenic.

[Bone Metastases - Pathophysiology, Diagnostic Testing and Therapy (Part 1)]. / Knochenmetastasen ­ Pathophysiologie, Diagnostik und Therapie (Teil 1).

In Germany and other European countries, cancer is the second most common cause of death after cardiovascular disease. Although 5-year survival rates for several types of cancer have significantly improved over the last 30 years, metastasis to the bone almost always leads to incurable disease. Aside from the rare primary bone tumours, the treatment of bone metastases now accounts for a major part of tumour orthopaedic workload and requires close interdisciplinary coordination between specialists in oncology, radiology and the discipline of the primary tumour entity. Due to improvements in oncological treatment regimes, long survival times can be achieved. Therefore, the management of so-called "SRE" (skeletal-related events) has gained importance, even in palliative situations. On the basis of a selective literature review, the following article points out the underlying pathophysiological processes of bone metastases and outlines different diagnostic approaches and their relevance in the current clinical setting.