Bone health issues in breast cancer survivors: a Medicare Current Beneficiary Survey (MCBS) study.

Purpose: Breast cancer treatments (chemotherapy and hormone therapy) can cause a rapid loss in bone mineral density, leading to osteoporosis and fractures later in life. Fortunately, preventative measures (vitamin D, exercise, etc.) can delay bone loss if employed early enough.

Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.

Lead remains a significant environmental toxin, and we believe we may have identified a novel target of lead toxicity in articular chondrocytes. These cells are responsible for the maintenance of joint matrix, and do so under the regulation of TGF-β signaling. As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-β signaling.

Ski inhibits TGF-β/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes.

Since transforming growing factor-β (TGF-β)/Smad signaling inhibits chondrocyte maturation, endogenous negative regulators of TGF-β signaling are likely also important regulators of the chondrocyte differentiation process. One such negative regulator, Ski, is an oncoprotein that is known to inhibit TGF-β/Smad3 signaling via its interaction with phospho-Smad3 and recruitment of histone deacetylases (HDACs) to the DNA binding complex. Based on this, we hypothesized that Ski inhibits TGF-β signaling and accelerates maturation in chondrocytes via recruitment of HDACs to transcriptional complexes containing Smads.

High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury.

Introduction: Increasing obesity and type 2 diabetes, in part due to the high-fat (HF) Western diet, parallels an increased incidence of osteoarthritis (OA). This study was undertaken to establish a causal relation between the HF diet and accelerated OA progression in a mouse model and to determine the relative roles of weight gain and metabolic dysregulation in this progression.

Methods: Five-week-old C57BL/6 mice were placed on HF (60% kcal) or low-fat (lean, 10% kcal) diets for 8 or 12 weeks before transecting the medial collateral ligament and excising a segment of the medial meniscus of the knee to initiate OA.

Targeting radioresistant osteosarcoma cells with parthenolide.

Osteosarcoma is a devastating tumor of bone, primarily affecting adolescents. Osteosarcoma tumors are notoriously radioresistant. Radioresistant cancers, including osteosarcoma, typically exhibit a considerable potential for relapse and development of metastases following treatment.

Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis.

There is no disease-modifying therapy for osteoarthritis, a degenerative joint disease that is projected to afflict more than 67 million individuals in the United States alone by 2030. Because disease pathogenesis is associated with inappropriate articular chondrocyte maturation resembling that seen during normal endochondral ossification, pathways that govern the maturation of articular chondrocytes are candidate therapeutic targets. It is well established that parathyroid hormone (PTH) acting via the type 1 PTH receptor induces matrix synthesis and suppresses maturation of chondrocytes.

The effect of various vitamin D supplementation regimens in breast cancer patients.

Vitamin D deficiency in the patients treated for breast cancer is associated with numerous adverse effects (bone loss, arthralgia, and falls). The first aim of this study was to assess vitamin D status, determined by 25-OH vitamin D levels, among women diagnosed with breast cancer according to demographic/clinical variables and bone mineral density (BMD). The second aim of this study was to evaluate the effect of daily low-dose and weekly high-dose vitamin D supplementation on 25-OH vitamin D levels.

Establishment of an index with increased sensitivity for assessing murine arthritis.

The goals of our study were to establish quantitative outcomes for assessing murine knee arthritis and develop an Arthritis Index that incorporates multiple outcomes into a single calculation that provides enhanced sensitivity. Using an accepted model of meniscal/ligamentous injury (MLI)-induced osteoarthritis (OA), we assessed mouse knee arthritis using several approaches. Histology-based methods were performed to visualize joint tissues including articular cartilage and subchondral bone.

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model.

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival.

The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy.

Soft tissue sarcoma (STS) is a rare malignancy that is generally resistant to chemotherapy. We investigated the ability of the histone deacetylase inhibitor vorinostat to sensitize STS cells versus normal fibroblasts to chemotherapy. Fibrosarcoma, leiomyosarcoma, and liposarcoma cells and normal fibroblasts were treated with vorinostat to determine effects on proliferation and basal apoptosis as measured by total cell number and cleaved caspase 3 staining.

Bone density changes after radiation for extremity sarcomas: exploring the etiology of pathologic fractures.

Purpose: The incidental irradiation (RT) of adjacent bone that takes place during treatment of soft tissue extremity sarcomas is generally presumed to "weaken" the bone by decreasing its density, which subsequently increases the risk for pathologic fracture. This investigation intended to assess the relative effects on bone density of both RT and diminished mechanical loading secondary to tumor-induced and therapy-induced functional extremity impairment.

Methods And Materials: 19 patients treated with surgical excision and RT for soft tissue extremity sarcomas had bone density measured using dual energy X-ray absorptiometry at four sites: the irradiated (A) and contralateral (B) bone, and an uninvolved bone (C) in the treated extremity and its contralateral counterpart (D).

Teriparatide therapy and beta-tricalcium phosphate enhance scaffold reconstruction of mouse femoral defects.

To investigate the efficacy of endocrine parathyroid hormone treatment on tissue-engineered bone regeneration, massive femoral defects in C57Bl/6 mice were reconstructed with either 100:0 or 85:15 poly-lactic acid (PLA)/beta-tricalcium phosphate (β-TCP) scaffolds (hereafter PLA or PLA/βTCP, respectively), which were fabricated with low porosity (<30%) to improve their structural rigidity. Experimental mice were treated starting at 1 week postop with daily subcutaneous injections of 40 μg/kg teriparatide until sacrifice at 9 weeks, whereas control mice underwent the same procedure but were injected with sterile saline. Bone regeneration was assessed longitudinally using planar X-ray and quantitative microcomputed tomography, and the reconstructed femurs were evaluated at 9 weeks either histologically or biomechanically to determine their torsional strength and rigidity.

Effects of a structured weight-bearing exercise program on bone metabolism among breast cancer survivors: a feasibility trial.

Purpose: Treatments for breast cancer, specifically hormonal therapy, accelerate bone loss (BL) among breast cancer survivors, leading to osteoporosis and an increase in fracture risk. Tai Chi Chuan (TCC) is a moderate form of weight-bearing exercise, equivalent to walking, and it has been shown to improve aerobic capacity and strength among breast cancer survivors and might also be effective in slowing bone loss in breast cancer survivors. This pilot study compared the influence of TCC with that of standard support therapy (ST; exercise control) on BL biomarkers among breast cancer survivors.

Beta-catenin, cartilage, and osteoarthritis.

The early cellular events during the development of osteoarthritis (OA) are accelerated articular chondrocyte maturation and extracellular matrix degradation, which are usually seen in the weight-bearing region of articular cartilage. The results of our recent studies from transgenic OA mouse models indicate that upregulation of beta-catenin signaling in articular chondrocytes is most likely responsible for the conversion of normal articular chondrocytes into maturing (arthritic) chondrocytes, which is associated with activation of chondrocyte maturational genes and matrix degradation. Conditional activation of the beta-catenin gene in articular chondrocytes leads to an OA-like phenotype.

Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage.

We have previously demonstrated that Smurf2 is highly expressed in human osteoarthritis (OA) tissue, and overexpression of Smurf2 under the control of the type II collagen promoter (Col2a1) induces an OA-like phenotype in aged Col2a1-Smurf2 transgenic mice, suggesting that Smurf2 is located upstream of a signal cascade which initiates OA development. However, the factors downstream of Smurf2 in this signal cascade and how Smurf2-induced OA is initiated are largely unknown. In this study, we further characterized the phenotypic changes in Col2a1-Smurf2 transgenic and WT articular cartilage from the postnatal stage to adulthood.

Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice.

Objective: To determine whether Smurf2, an E3 ubiquitin ligase known to inhibit transforming growth factor beta (TGFbeta) signaling, is expressed in human osteoarthritic (OA) cartilage and can initiate OA in mice.

Methods: Human OA cartilage was obtained from patients undergoing knee arthroplasty. Samples were graded histologically using the Mankin scale and were examined immunohistochemically for Smurf2 expression.

Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice.

Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/beta-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for beta-catenin in this disease has not been reported.

Erythropoietin accelerates functional recovery after peripheral nerve injury.

Background: Erythropoietin is a naturally occurring hormone with multiple effects on a number of different cell types. Recent data have suggested neuroprotective and perhaps even neurotrophic roles for erythropoietin. We hypothesized that these functional effects could be demonstrable in standard models of peripheral nerve injury.

Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction.

Objective: Osteoarthritis is a degenerative joint disease whose molecular mechanism is currently unknown. Wnt/beta-catenin signaling has been demonstrated to play a critical role in the development and function of articular chondrocytes. To determine the role of beta-catenin signaling in articular chondrocyte function, we generated Col2a1-ICAT-transgenic mice to inhibit beta-catenin signaling in chondrocytes.

Quantification of massive allograft healing with dynamic contrast enhanced-MRI and cone beam-CT: a pilot study.

Although massive allografts are widely used for reconstruction of critical defects in long bones caused by tumor or trauma, many will have inadequate long-term outcomes. Toward a tissue engineering solution to this problem, we developed experimental stem cell and gene therapy adjuvants that induce angiogenesis, osteogenesis, and remodeling of the structural allografts. We present data from pilot studies to show the utility of dynamic contrast enhanced MRI (DCE-MRI) to quantify vascularity after femoral osteotomy in a canine femur model and cone beam CT (CB-CT) to quantify bone volume in a patient after composite prosthetic-allograft reconstructive surgery.

Teriparatide (1-34 human PTH) regulation of osterix during fracture repair.

Based on remarkable success of PTH as an anabolic drug for osteoporosis, case reports of off-label use of teriparatide (1-34 PTH) in patients with complicated fractures and non-unions are emerging. We investigated the mechanisms underlying PTH accelerated fracture repair. Bone marrow cells from 7 days 40 microg/kg of teriparatide treated or saline control mice were cultured and Osx and osteoblast phenotypic gene expression assessed by real-time RT-PCR in these cells.

Regulation of embryonic endochondral ossification by Smurf2.

Smurf2 is an E3 ubiquitin ligase that targets TGF-beta receptor activated Smad2 and Smad3 for the proteasome in primary articular chondrocytes, thus stimulating their hypertrophic differentiation. Comparatively, how Smurf2 functions in growth plate chondrocytes in a developing long bone is an open question. In this study, we measured the mRNA levels of endogenous Smurf2 and type X collagen in chick growth plate at different embryonic stages to monitor the correlation between the level of Smurf2 expression and chondrocyte maturational stage.

Overexpression of Smurf2 stimulates endochondral ossification through upregulation of beta-catenin.

Unlabelled: Ectopic expression of Smurf2 in chondrocytes and perichondrial cells accelerated endochondral ossification by stimulating chondrocyte maturation and osteoblast development through upregulation of beta-catenin in Col2a1-Smurf2 embryos. The mechanism underlying Smurf2-mediated morphological changes during embryonic development may provide new mechanistic insights and potential targets for prevention and treatment of human osteoarthritis.

Introduction: Our recent finding that adult Col2a1-Smurf2 mice have an osteoarthritis-like phenotype in knee joints prompted us to examine the role of Smurf2 in the regulation of chondrocyte maturation and osteoblast differentiation during embryonic endochondral ossification.

Institutional barriers to the orthopaedic clinician-scientist.

The clinician-scientist faces many career barriers that changes in medicine over the past two decades have accentuated. Political, socioeconomic, and cultural changes in medicine have increased financial pressures on physicians and hospitals, negatively impacting the ability of clinicians to pursue research activities. Examples of institutional barriers include pressure on physicians to increase clinical productivity to help offset rising costs and declining reimbursements, inadequate resources and structures to protect research time, a lack of consideration of the importance of spatial colocalization of interacting researchers and clinicians, insufficient focus on integrating clinician-scientists into research teams, and inadequate accessibility of administrative research infrastructure.

Continuing competency in orthopaedics: the future of recertification.

The American Board of Orthopaedic Surgery implemented a recertification program in 1986. This process has expanded to include a number of examination pathways that take into account subspecialty practices. Over the past two decades, general competencies of physicians have been defined and programs for evaluation and maintenance of these competencies developed.