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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Regulates Osteoclast Differentiation via the Ca2+ /NFATc1 Axis.

DC-STAMP is a multi-pass transmembrane protein essential for cell-cell fusion between osteoclast precursors during osteoclast (OC) development. DC-STAMP-/- mice have mild osteopetrosis and form mononuclear cells with limited resorption capacity. The identification of an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) on the cytoplasmic tail of DC-STAMP suggested a potential signaling function. The absence of a known DC-STAMP ligand, however, has hindered the elucidation of downstream signaling pathways. To address this problem, we engineered a light-activatable DC-STAMP chimeric molecule in which light exposure mimics ligand engagement that can be traced by downstream Ca2+ signaling. Deletion of the cytoplasmic ITIM resulted in a significant elevation in the amplitude and duration of intracellular Ca2+ flux. Decreased NFATc1 expression in DC-STAMP-/- cells was restored by DC-STAMP over-expression. Multiple biological phenotypes including cell-cell fusion, bone erosion, cell mobility, DC-STAMP cell surface distribution, and NFATc1 nuclear translocation were altered by deletion of the ITIM and adjacent amino acids. In contrast, mutations on each of the tyrosine residues surrounding the ITIM showed no effect on DC-STAMP function. Collectively, our results suggest that the ITIM on DC-STAMP is a functional motif that regulates osteoclast differentiation through the NFATc1/Ca2+ axis. J. Cell. Physiol. 232: 2538-2549, 2017. © 2016 Wiley Periodicals, Inc.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

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.

A 3- to 18-Year Follow-Up of Revision Total Hip Arthroplasty With Impacted Bone Allografts and Cemented Lubinus SP II Stem. Clinical, Radiographic, and Survivorship Analysis With Comparison to the Literature.

BACKGROUND: We present the first medium- to long-term follow-up of revision total hip arthroplasty using impaction bone grafting (IBG) combined with the matte and collared Lubinus SP II stem for cases of severe osteolysis and stem loosening. METHODS: Sixty-nine femoral revisions were identified for 67 patients consecutively operated with revision femoral arthroplasty using IBG and a cemented Lubinus SP II stem. The mean age was 69 years (standard deviation, 9.9). We retrospectively analyzed 68 cases (1 was lost to follow-up). At the time of the revision surgery, all had substantial femoral bone loss. Fifteen of the revisions were performed due to deep infection. The patients were analyzed by clinical score and radiography. RESULTS: At follow-up, 4 femoral components (6%) had been rerevised or assessed as failure. Of these 4, 3 were assessed as mechanical failure, and 1 for dislocation; none was for infection. Three cups (4%) had been revised for dislocation; 1 of these also had a stem exchange. Three cases (4%) had been reoperated for a periprosthetic fracture in distal femur without stem exchange. Radiologic results were excellent and the clinical Merle d'Aubignè-Postel score had improved from a mean of 12.2 preoperatively to 17.5 at follow-up. CONCLUSION: IBG combined with the Lubinus SP II stem is safe and results in a low rate of periprosthetic fractures and dislocations. The medium- to long-term clinical result was excellent, with regeneration of living bone in the femur.

Interleukin 26 suppresses receptor activator of nuclear factor κB ligand induced osteoclastogenesis via down-regulation of nuclear factor of activated T-cells, cytoplasmic 1 and nuclear factor κB activity.

OBJECTIVE: IL-26 has been shown to have high expression in RA. However, the effects of IL-26 on bone destruction in RA have not been evaluated. The aim of this study was to investigate the effects and mechanisms of IL-26 on RANK ligand (RANKL)-induced osteoclastogenesis. METHODS: We treated cells with IL-26 in RANKL-induced oseteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed by pit formation assay and F-actin ring formation. The mechanism of the inhibition was studied by biochemical analyses such as RT-PCR, immunofluorescence staining and immunoblotting. In addition, cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: IL-26 inhibited RANKL-induced TRAP-positive multinucleated cells and inhibited RANKL-induced nuclear factor κB (NF-κB) activation and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation in RAW264.7 cells. Also, IL-26 significantly inhibited the bone-resorbing activity and F-actin ring formation ability of mature osteoclasts. Moreover, IL-26 suppressed RANKL-induced mitogen-activated protein kinase activation and NFATc1 downstream gene expression. CONCLUSION: We suggest that the inhibitory activity of IL-26 on osteoclastogenesis is via down-regulation of RANKL-induced NF-κB and NFATc1 expression. Our results suggest IL-26 as a possible new remedy against osteolytic bone destruction.

NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms.

Activating-mutations in NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) cause neonatal-onset multisystem inflammatory disease. However, the ontogeny of skeletal anomalies in this disorder is poorly understood. Mice globally expressing the D301N mutation in Nlrp3 (D303N in human) model the human phenotype, including systemic inflammation and skeletal deformities. To gain insights into the skeletal manifestations, we generated mice in which the expression of D301N Nlrp3 (Nlrp3( D301N)) is restricted to myeloid cells. These mice exhibit systemic inflammation and severe osteopenia (∼ 60% lower bone mass) similar to mice globally expressing the knock-in mutation, consistent with the paradigm of innate immune-driven cryopyrinopathies. Because systemic inflammation may indirectly affect bone homeostasis, we engineered mice in which Nlrp3( D301N) is expressed specifically in osteoclasts, the cells that resorb bone. These mice also develop ∼ 50% lower bone mass due to increased osteolysis, but there is no systemic inflammation and no change in osteoclast number. Mechanistically, aside from its role in IL-1ß maturation, Nlrp3( D301N) expression enhances osteoclast bone resorbing ability through reorganization of actin cytoskeleton while promoting the degradation of poly(ADP-ribose) polymerase 1, an inhibitor of osteoclastogenesis. Thus, NLRP3 inflammasome activation is not restricted to the production of proinflammatory mediators but also leads to cytokine-autonomous responses.

Wear and Osteolysis of Highly Crosslinked Polyethylene at 10 to 14 Years: The Effect of Femoral Head Size.

BACKGROUND: Highly crosslinked polyethylene (XLPE) was introduced to decrease periprosthetic osteolysis related to polyethylene wear, a major reason for revision of total hip arthroplasty. However, there are few reports of wear and osteolysis at 10 years postoperatively. QUESTIONS/PURPOSES: (1) What are the linear and volumetric wear rates of XLPE at 10 to 14 years? (2) What is the relationship among linear wear, volumetric wear, and femoral head size? (3) What proportion of hips developed osteolysis and was there a relationship between osteolysis and femoral head size or polyethylene wear? METHODS: We evaluated a previously reported cohort of 84 hips (72 patients) with one design of an uncemented acetabular component and one electron beam 10-kGy irradiated and remelted XLPE at a mean followup of 11 years (range, 10-14 years). The choice of femoral head size was based on several factors, including the outer diameter size of the acetabular component implanted, the perceived risk of dislocation (including the history of alcohol abuse and patient age), and liner availability from the manufacturer. The femoral head sizes used were 26 mm in 10 hips (12%), 28 mm in 31 hips (37%), 32 mm in 31 hips (37%), 36 mm in eight hips (10%), and 40 mm in four hips (5%). Measurements of linear and volumetric wear were performed in one experienced laboratory by the Martell method and analyzed using the first-to-last method. Standard radiographs, with additional Judet views, were used to detect periprosthetic osteolysis. Statistical analysis of wear and osteolysis compared with head size was performed. RESULTS: For the entire cohort, the median linear wear rate as 0.024 mm/year (95% confidence interval [CI], 0.016-0.030) and the median volumetric wear rate was 12.19 mm(3)/year (95% CI, 6.6-15.7). With the numbers available, we found no association between femoral head size and linear wear rate. However, larger femoral heads were associated with more volumetric wear; 36/40-mm femoral heads had higher volumetric wear (median 26.1; 95% CI, 11.3-47.1) than did 26-mm heads (median 3.1; 95% CI, 0.7-12.3), 28-mm heads (median 12.3; 95% CI, 3.0-19.3), and 32-mm heads (median 12.9; 95% CI, 6.6-16.8; p = 0.02). Small osteolytic lesions were noted in 12 hips (14%), but with the numbers available, there was no association with head size or volumetric wear rates. CONCLUSIONS: This uncemented acetabular component and this particular XLPE had low rates of linear and volumetric wear. Small osteolytic lesions were noted at 10 to 14 years but were not related to femoral head size or linear or volumetric wear rates. We recommend additional longer-term clinical followup studies and perhaps alternative imaging studies of patients with XLPE and osteolysis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Distal clavicular osteolysis in adults: association with bench pressing intensity.

OBJECTIVES: To investigate the association between distal clavicular osteolysis (DCO) and bench pressing intensity. METHODS: From a retrospective review of MRI shoulder reports of individuals between 20 and 40 years of age, 262 male patients with DCO and 227 age-matched male patients without DCO were selected. All patients had completed a bench pressing questionnaire. The patients' bench pressing frequency (times per week), duration (years of bench pressing), bench pressing weight (maximum bench pressing weight with one repetition = 1RM) and the ratio of bench pressing weight to body weight were compared between both groups using Chi-square and Mann-Whitney tests. RESULTS: The results showed that 56 % (146/262) of patients with DCO were high-intensity bench pressers (1RM more than 1.5 times the body weight) compared to 6 % (14/227) in patients without DCO. High-intensity bench pressing was a risk factor for DCO (OR = 19; 95 %CI = 11-35; p < 0.001). Low-intensity bench pressing (1RM less than 1.5 times the body weight) was not a risk factor for DCO (OR = 0.6; 95 % CI = 0.4-0.8). High frequency (>1×/week) and duration (>5 years) of bench pressing were risk factors. In bench pressers who suffered from DCO, the mean 1RM was 283 lbs (±SD 57) compared to 209 lbs (±SD 60) in bench pressers not affected by DCO (p < 0.001, Mann-Whitney). CONCLUSIONS: High-intensity, but not low-intensity bench pressing is a risk factor for DCO.

Remplissage of an Off-track Hill-Sachs Lesion Is Necessary to Restore Biomechanical Glenohumeral Joint Stability in a Bipolar Bone Loss Model.

PURPOSE: To validate the glenoid track concept in a cadaveric bipolar bone loss model and to test whether "on-track" and "off-track" lesions can be stabilized with Bankart repair (BR) with or without Hill-Sachs remplissage (HSR). METHODS: Eight fresh-frozen cadaveric shoulders were tested in a custom apparatus with passive axial rotation and then progressive translational loading (10 to 40 N) at mid-range (60°) and end-range external rotation (90°). Injury conditions included glenoid bone loss of 15% with on-track (15%) and off-track (30%) Hill-Sachs lesions. Repair conditions included BR with HSR and BR without HSR. RESULTS: For on-track lesions, engagement occurred with translation testing in one shoulder (12.5%) at end-range rotation. After BR, engagement was prevented for this shoulder. For off-track lesions, engagement with translation testing occurred in 8 shoulders (100%) at end-range rotation and in 6 (75%) at mid-range rotation. After BR, engagement was prevented in 4 of 6 engaging shoulders (67%) at mid-range rotation but was prevented in zero of 8 (0%) at end-range rotation. Adding HSR prevented engagement in all 14 engaging shoulders with off-track lesions (100%). BR with HSR resulted in supraphysiological stiffness for off-track lesions at mid- and end-range rotation (13.3 N/m vs 7.0 N/m and 10.0 N/m vs 5.0 N/m, P = .0002) and for on-track lesions at end-range rotation (10.1 N/m vs 5.0 N/m, P = .0002). Stiffness of BR with HSR was not different from the intact shoulder for on-track lesions at mid-range rotation (7.2 N/m vs 7.0 N/m, P > .99). CONCLUSIONS: The patterns of engagement of Hill-Sachs lesions with a 15% glenoid defect in this model give support to the glenoid track concept. BR plus remplissage resulted in supraphysiological shoulder stiffness but was necessary to prevent engagement of off-track bipolar bone lesions. CLINICAL RELEVANCE: This biomechanical study provides evidence to aid in surgical decision making by examining the effects of bipolar bone loss and soft-tissue reconstruction on shoulder stability.