Derek F. Amanatullah

The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways.

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20–30% of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the β-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of β1 and β3integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide −54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3β (GSK-3β) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.

PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure

Transcriptional repression mechanisms are important during differentiation of multipotential hematopoietic progenitors, where they are thought to regulate lineage commitment and to extinguish alternative differentiation programs. PU.1 and GATA‐1 are two critical hematopoietic transcription factors that physically interact and mutually antagonize each others transcriptional activity and ability to promote myeloid and erythroid differentiation, respectively. We find that PU.1 inhibits the erythroid program by binding to GATA‐1 on its target genes and organizing a complex of proteins that creates a repressive chromatin structure containing lysine‐9 methylated H3 histones and heterochromatin protein 1. Although these features are thought to be stable aspects of repressed chromatin, we find that silencing of PU.1 expression leads to removal of the repression complex, loss of the repressive chromatin marks and reactivation of the erythroid program. This process involves incorporation of the replacement histone variant H3.3 into nucleosomes. Repression of one transcription factor bound to DNA by another transcription factor not on the DNA represents a new mechanism for downregulating an alternative gene expression program during lineage commitment of multipotential hematopoietic progenitors.

Comparison of Surgical Outcomes and Implant Wear Between Ceramic-Ceramic and Ceramic-Polyethylene Articulations in Total Hip Arthroplasty

The results of a prospective multicenter trial comparing 357 hips randomized to total hip arthroplasty with either ceramic-ceramic or ceramic-polyethylene couplings are presented. No statistically significant difference in clinical outcomes scores between the ceramic-ceramic and ceramic-polyethylene groups was observed at any time interval. The mean linear rate was statistically lower (P < .001) in the ceramic-ceramic group (30.5 μm/year) when compared with the ceramic-polyethylene group (218.2 μm/year). The rates of ceramic implant fracture (2.6%) and audible component-related noise (3.1%) were statistically higher in the ceramic-ceramic group when compared with the ceramic-polyethylene group (P < .05). Lastly, there was no statistically significant difference in the dislocation or revision rate between the groups at the time of last clinical follow-up.

Giant cell tumor of bone.

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Identify at-risk populations for giant cell tumor of bone. 2. Recognize the biology that drives giant cell tumor of bone. 3. Describe modern surgical and adjuvant techniques to effectively treat giant cell tumor of bone. 4. Recognize the complications associated with radiation therapy, poor resection, and adjuvant treatments. Giant cell tumor of bone (GCT) is a benign, locally aggressive bone tumor. Giant cell tumor of bone primarily affects the young adult patient population. The natural history of GCT is progressive bone destruction leading to joint deformity and disability. Surgery is the primary mode of treatment, but GCT has a tendency to recur locally despite a range of adjuvant surgical options. Pulmonary metastasis has been described. However, systemic spread of GCT rarely becomes progressive, leading to death. This review presents the clinicopathologic features of GCT and a historical perspective that highlights the current rationale and controversies regarding the treatment of GCT.

Acetabular Fractures: What Radiologists Should Know and How 3D CT Can Aid Classification

Correct recognition, description, and classification of acetabular fractures is essential for efficient patient triage and treatment. Acetabular fractures may result from high-energy trauma or low-energy trauma in the elderly. The most widely used acetabular fracture classification system among radiologists and orthopedic surgeons is the system of Judet and Letournel, which includes five elementary (or elemental) and five associated fractures. The elementary fractures are anterior wall, posterior wall, anterior column, posterior column, and transverse. The associated fractures are all combinations or partial combinations of the elementary fractures and include transverse with posterior wall, T-shaped, associated both column, anterior column or wall with posterior hemitransverse, and posterior column with posterior wall. The most unique fracture is the associated both column fracture, which completely dissociates the acetabular articular surface from the sciatic buttress. Accurate categorization of acetabular fractures is challenging because of the complex three-dimensional (3D) anatomy of the pelvis, the rarity of certain acetabular fracture variants, and confusing nomenclature. Comparing a 3D image of the fractured acetabulum with a standard diagram containing the 10 Judet and Letournel categories of acetabular fracture and using a flowchart algorithm are effective ways of arriving at the correct fracture classification. Online supplemental material is available for this article.

Ras regulation of cyclin D1 promoter.

Publisher Summary This chapter focuses on the Ras regulation of Cyclin D 1 promoter. Cyclin D l, the regulatory subunit of cyclin-dependent kinases (CDK) 4 and 6, is required for, and capable of, shortening, the G j phase of the cell cycle through the formation of holoenzyme complexes (cyclin-CDK) that phosphorylate retinoblastoma protein (pRB). Ras transformation is inhibited by antisense to cyclin D1 mRNA. The Ras-related proteins, Rac and Rho, also induce the cyclin D1 promoter. Racl regulates several distinct pathways; no single Rac effect is necessary or sufficient for transformation. Platelet-derived growth factor (PDGF) activates the extracellular signal-regulated kinase (ERK) pathway, which has been shown to induce DNA synthesis, increase cyclin D1 protein levels, and stimulate the transcription of the cyclin D1 promoter. Therefore, Rac 1 is neither necessary nor sufficient to activate the ERK pathway, suggesting that Rac regulation of cyclin D1 is ERK independent. The cyclin DI promoter is used as a molecular probe of the signal transduction pathways involved in Ras signaling. The valid assessment of promoter activation by Ras requires the use of a reporter system that is not itself responsive to components of the Ras signaling pathway.

The biological response to orthopaedic implants for joint replacement: Part I: Metals.

Joint replacement is a commonly performed, highly successful orthopaedic procedure, for which surgeons have a large choice of different materials and implant designs. The materials used for joint replacement must be both biologically acceptable to minimize adverse local tissue reactions, and robust enough to support weight bearing during common activities of daily living. Modern joint replacements are made from metals and their alloys, polymers, ceramics, and composites. This review focuses on the biological response to the different biomaterials used for joint replacement. In general, modern materials for joint replacement are well tolerated by the body as long as they are in bulk (rather than in particulate or ionic) form, are mechanically stable and noninfected. If the latter conditions are not met, the prosthesis will be associated with an acute/chronic inflammatory reaction, peri-prosthetic osteolysis, loosening and failure. This article (Part 1 of 2) is dedicated to the use of metallic devices in orthopaedic surgery including the associated biological response to metallic byproducts is a review of the basic science literature regarding this topic.

Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis

OBJECTIVE Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. DESIGN Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. RESULTS Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. CONCLUSION Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

Biomechanical properties of volar hybrid and locked plate fixation in distal radius fractures

PURPOSE We compare the biomechanical properties of a volar hybrid construct to an all-locking construct in an osteoporotic and normal comminuted distal radius fracture model. METHODS Groups of 28 normal, 28 osteoporotic, and 28 over-drilled osteoporotic left distal radius synthetic bones were used. The normal group consisted of synthetic bone with a standard foam core. The osteoporotic group consisted of synthetic bone with decreased foam core density. The over-drilled osteoporotic group consisted of synthetic bone with decreased foam core density and holes drilled with a 2.3 mm drill, instead of the standard 2.0 mm drill, to simulate the lack of purchase in osteoporotic bone. Within each group, 14 synthetic bones were plated with a volar locking plate using an all-locking screw construct, and 14 synthetic bones were plated with a volar locking plate using a hybrid screw construct (ie, both locking and nonlocking screws). A 1-cm dorsal wedge osteotomy was created with the apex 2 cm from the volar surface of the lunate facet. Each specimen was mounted to a materials testing machine, using a custom-built, standardized axial compression jig. Axial compression was delivered at 1 N/s over 3 cycles from 20 N to 100 N to establish stiffness. Each sample was stressed to failure at 1 mm/s until 5 mm of permanent deformation occurred. RESULTS Our results show no difference in construct stiffness and load at failure between the all-locking and hybrid constructs in the normal, osteoporotic, or over-drilled osteoporotic synthetic bone models. All specimens failed by plate bending at the osteotomy site with loss of height. CLINICAL RELEVANCE Although volar locking plates are commonly used for the treatment of distal radius fractures, the ideal screw configuration has not been determined. Hybrid fixation has comparable biomechanical properties to all locking constructs in the fixation of metaphyseal fractures about the knee and shoulder and might also have a role in the fixation of distal radius fractures.

Hip Resurfacing Arthroplasty: A Review of the Evidence for Surgical Technique, Outcome, and Complications

Hip resurfacing arthroplasty has reemerged as a valid reconstruction option for the osteoarthritic hip. Patient selection is critical for excellent surgical outcomes, especially when compared with total hip arthroplasty. However, concerns regarding surgical technique and postsurgical complications persist. The authors review the evidence for surgical technique, outcomes, and complications related to modern metal-on-metal hip resurfacing arthroplasty.