Publications by authors named "Laurie K McCauley"

106 Publications

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J Am Dent Assoc 2020 08;151(8):555

Dean, School of Dentistry, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1016/j.adaj.2020.06.009DOI Listing
August 2020

Three-Dimensional Electrodeposition of Calcium Phosphates on Porous Nanofibrous Scaffolds and Their Controlled Release of Calcium for Bone Regeneration.

ACS Appl Mater Interfaces 2020 Jul 13;12(29):32503-32513. Epub 2020 Jul 13.

Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.

To mimic the bone matrix of mineralized collagen and to impart microporous structure to facilitate cell migration and bone regeneration, we developed a nanofibrous (NF) polymer scaffold with highly interconnected pores and three-dimensional calcium phosphate coating utilizing an electrodeposition technique. The mineral content, morphology, crystal structure, and chemical composition could be tailored by adjusting the deposition temperature, voltage, and duration. A higher voltage and a higher temperature led to a greater rate of mineralization. Furthermore, nearly linear calcium releasing kinetics was achieved from the mineralized 3D scaffolds. The releasing rate was controlled by varying the initial electrodeposition conditions. A higher deposition voltage and temperature led to slower calcium release, which was associated with the highly crystalline and stoichiometric hydroxyapatite content. This premineralized NF scaffold enhanced bone regeneration over the control scaffold in a subcutaneous implantation model, which was associated with released calcium ions in facilitating osteogenic cell proliferation.
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http://dx.doi.org/10.1021/acsami.0c11003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384879PMC
July 2020

Contribution of Macrophages and T Cells in Skeletal Metastasis.

Cancers (Basel) 2020 Apr 20;12(4). Epub 2020 Apr 20.

Biomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada, Ensenada, BC 22860, México.

Bone is a common site for metastases with a local microenvironment that is highly conducive for tumor establishment and growth. The bone marrow is replete with myeloid and lymphoid linage cells that provide a fertile niche for metastatic cancer cells promoting their survival and growth. Here, we discuss the role of macrophages and T cells in pro- and anti-tumoral mechanisms, their interaction to support cancer cell growth, and their contribution to the development of skeletal metastases. Importantly, immunotherapeutic strategies targeting macrophages and T cells in cancer are also discussed in this review as they represent a great promise for patients suffering from incurable bone metastases.
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http://dx.doi.org/10.3390/cancers12041014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226332PMC
April 2020

Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance.

Cells 2020 02 12;9(2). Epub 2020 Feb 12.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.

The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory response that accelerated metastatic tumor growth in bone. To evaluate the microenvironmental impact of macrophages and their efferocytic function, we compared peritoneal macrophages (P-MΦ) versus bone marrow-derived macrophages (BM-MΦs) using an efferocytosis in vitro model. The capability to engulf apoptotic prostate cells was similar in BM-MΦs and P-MΦs. Ex vivo analysis of BM-MΦs showed an M2-like phenotype compared with a predominantly M1-like phenotype in P-MΦs. A distinct gene and protein expression profile of pro-inflammatory cytokines was found in BM-MΦs as compared with P-MΦs engulfing apoptotic prostate cancer cells. Importantly, the reprogramming of BM-MΦs toward an M1-like phenotype mitigated their inflammatory cytokine expression profile. In conclusion, BM-MΦs and P-MΦs are both capable of efferocytosing apoptotic prostate cancer cells; however, BM-MΦs exert increased inflammatory cytokine expression that is dependent upon the M2 polarization stage of macrophages. These findings suggest that bone marrow macrophage efferocytosis of apoptotic cancer cells maintains a unique pro-inflammatory microenvironment that may support a fertile niche for cancer growth. Finally, bone marrow macrophage reprogramming towards M1-type by interferon-γ (IFN-γ) induced a significant reduction in the efferocytosis-mediated pro-inflammatory signature.
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http://dx.doi.org/10.3390/cells9020429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072562PMC
February 2020

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020

Effects of Intermittent Administration of Parathyroid Hormone and Parathyroid Hormone-Related Protein on Fracture Healing: A Narrative Review of Animal and Human Studies.

JBMR Plus 2019 Dec 22;3(12):e10250. Epub 2019 Nov 22.

Department of Periodontics and Oral Medicine, School of Dentistry University of Michigan Ann Arbor MI USA.

Intermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH-related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up-to-date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to "regeneration," "implant," and "distraction osteogenesis" were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894727PMC
December 2019

Efferocytosis and prostate cancer skeletal metastasis: implications for intervention.

Oncoscience 2018 May 29;5(5-6):174-176. Epub 2018 Jun 29.

Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI 48109-1078, USA.

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http://dx.doi.org/10.18632/oncoscience.440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049312PMC
May 2018

Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide.

FASEB J 2018 07 22;32(7):3730-3741. Epub 2018 Feb 22.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

A prolonged increase in proinflammatory cytokines is associated with osteoporotic and autoimmune bone loss and, conversely, anti-inflammatory pathways are associated with protection against bone loss. Milk fat globule-epidermal growth factor (MFG-E)-8 is a glycoprotein that is proresolving, regulates apoptotic cell clearance, and has been linked to autoimmune disease and skeletal homeostasis. The role of MFG-E8 in the young vs. adult skeleton was determined in mice deficient in MFG-E8 (KO). In vivo, trabecular bone was similar in MFG-E8KO and wild-type (WT) mice at 6 and 16 wk, whereas 22 wk adult MFG-E8KO mice displayed significantly reduced trabecular BV/TV. The number of osteoclasts per bone surface was increased in 22-wk MFG-E8 KO vs. WT mice, and recombinant murine MFG-E8 decreased the number and size of osteoclasts in vitro. Adult MFG-E8KO spleen weight:body weight was increased compared with WT, and flow cytometric analysis showed significantly increased myeloid-derived suppressor cells (CD11bGR-1) and neutrophils (CD11bLy6G) in MFG-E8KO bone marrow, suggesting an inflammatory phenotype. PTH-treated MFG-E8KO mice showed a greater anabolic response (+124% BV/TV) than observed in PTH-treated WT mice (+64% BV/TV). These data give insight into the role of MFG-E8 in the adult skeleton and suggest that anabolic PTH may be a valuable therapeutic approach for autoimmune-associated skeletal disease.-Michalski, M. N., Seydel, A. L., Siismets, E. M., Zweifler, L. E., Koh, A. J., Sinder, B. P., Aguirre, J. I., Atabai, K., Roca, H., McCauley, L. K. Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide.
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http://dx.doi.org/10.1096/fj.201701238RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998979PMC
July 2018

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.

J Clin Invest 2018 01 27;128(1):248-266. Epub 2017 Nov 27.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.
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http://dx.doi.org/10.1172/JCI92466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749545PMC
January 2018

The Future of Dental Schools in Research Universities and Academic Health Centers.

J Dent Educ 2017 Sep;81(9):eS91-eS96

Dr. McCauley is Dean and William K. and May Anne Najjar Professor of Dentistry, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry and Professor, Department of Pathology, University of Michigan Medical School.

As a profession, dentistry is at a point of discernible challenge as well as incredible opportunity in a landscape of evolving changes to health care, higher education, and evidence-based decision making. Respecting the past yet driving forward, a well-mapped future course is critical. Orchestrating this course in a collaborative manner is essential for the visibility, well-being, and potentially the existence of the dental profession. The research performed in dental institutions needs to be contemporary, aligned with biomedical science in general, and united with other disciplines. Dentistry is at risk of attrition in the quality of its research and discovery mission if participation with bioscience colleagues in the collaborative generation of new knowledge is underoptimized. A fundamental opportunity dentistry has is to contribute via its position in academic health centers. Rigorous research as to the impact of interprofessional education and collaborative care on population health outcomes provides significant potential for the dental profession to participate and/or lead such evidence-centered efforts. It is imperative that academic dental institutions are part of interdisciplinary and transdisciplinary organizations that move health care into its new day. Strategizing diversity by bringing together people who have different ways of seeing problems to share perspectives, heuristics, interpretations, technologies, and predictive models across disciplines will lead to impactful progress. Academic dental institutions are a natural part of an emphasis on translational research and acceleration of implementing new scientific discoveries. Dentistry needs to remain an essential and integrated component of higher education in the health professions; doing so necessitates deliberate, respectful, and committed change. This article was written as part of the project "Advancing Dental Education in the 21 Century."
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http://dx.doi.org/10.21815/JDE.017.039DOI Listing
September 2017

Bone Mass Is Compromised by the Chemotherapeutic Trabectedin in Association With Effects on Osteoblasts and Macrophage Efferocytosis.

J Bone Miner Res 2017 Oct 31;32(10):2116-2127. Epub 2017 Aug 31.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Macrophages have established roles supporting bone formation. Despite their professional phagocytic nature, the role of macrophage phagocytosis in bone homeostasis is not well understood. Interestingly, apoptosis is a pivotal feature of cellular regulation and the primary fate of osteoblasts is apoptosis. Efferocytosis (phagocytosis of apoptotic cells) is a key physiologic process for the homeostasis of many tissues, and is associated with expression of osteoinductive factors. To test effects of macrophage depletion and compromised phagocytosis on bone, 16-week-old male C57BL/6J mice were treated with trabectedin-a chemotherapeutic with established anti-macrophage effects. Trabectedin treatment reduced F4/80+ and CD68+ macrophages in the bone marrow as assessed by flow cytometry, osteal macrophages near the bone surface, and macrophage viability in vitro. Trabectedin treatment significantly reduced marrow gene expression of key phagocytic factors (Mfge8, Mrc1), and macrophages from treated mice had a reduced ability to phagocytose apoptotic mimicry beads. Macrophages cultured in vitro and treated with trabectedin displayed reduced efferocytosis of apoptotic osteoblasts. Moreover, efferocytosis increased macrophage osteoinductive TGF-β production and this increase was inhibited by trabectedin. Long-term (6-week) treatment of 16-week-old C57BL/6J mice with trabectedin significantly reduced trabecular BV/TV and cortical BMD. Although trabectedin reduced osteoclast numbers in vitro, osteoclast surface in vivo was not altered. Trabectedin treatment reduced serum P1NP as well as MS/BS and BFR/BS, and inhibited mineralization and Runx2 gene expression of osteoblast cultures. Finally, intermittent PTH 1-34 (iPTH) treatment was administered in combination with trabectedin, and iPTH increased trabecular bone volume fraction (BV/TV) in trabectedin-treated mice. Collectively, the data support a model whereby trabectedin significantly reduces bone mass due to compromised macrophages and efferocytosis, but also due to direct effects on osteoblasts. This data has immediate clinical relevance in light of increasing use of trabectedin in oncology. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640484PMC
October 2017

Immune mediators in the tumor microenvironment of prostate cancer.

Chin J Cancer 2017 Mar 14;36(1):29. Epub 2017 Mar 14.

Department of Urology and Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA.

Prostate cancer tissue is composed of both cancer cells and host cells. The milieu of host components that compose the tumor is termed the tumor microenvironment (TME). Host cells can be those derived from the tissue in which the tumor originates (e.g., fibroblasts and endothelial cells) or those recruited, through chemotactic or other factors, to the tumor (e.g., circulating immune cells). Some immune cells are key players in the TME and represent a large proportion of non-tumor cells found within the tumor. Immune cells can have both anti-tumor and pro-tumor activity. In addition, crosstalk between prostate cancer cells and immune cells affects immune cell functions. In this review, we focus on immune cells and cytokines that contribute to tumor progression. We discuss T-regulatory and T helper 17 cells and macrophages as key modulators in prostate cancer progression. In addition, we discuss the roles of interleukin-6 and receptor activator of nuclear factor kappa-B ligand in modulating prostate cancer progression. This review highlights the concept that immune cells and cytokines offer a potentially promising target for prostate cancer therapy.
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http://dx.doi.org/10.1186/s40880-017-0198-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351274PMC
March 2017

Macrophages and skeletal health.

Pharmacol Ther 2017 Jun 7;174:43-54. Epub 2017 Feb 7.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States. Electronic address:

Bone is in a constant state of remodeling, a process which was once attributed solely to osteoblasts and osteoclasts. Decades of research has identified many other populations of cells in the bone that participate and mediate skeletal homeostasis. Recently, osteal macrophages emerged as vital participants in skeletal remodeling and osseous repair. The exact mechanistic roles of these tissue-resident macrophages are currently under investigation. Macrophages are highly plastic in response to their micro-environment and are typically classified as being pro- or anti-inflammatory (pro-resolving) in nature. Given that inflammatory states result in decreased bone mass, proinflammatory macrophages may be negative regulators of bone turnover. Pro-resolving macrophages have been shown to release anabolic factors and may present a target for therapeutic intervention in inflammation-induced bone loss and fracture healing. The process of apoptotic cell clearance, termed efferocytosis, is mediated by pro-resolving macrophages and may contribute to steady-state bone turnover as well as fracture healing and anabolic effects of osteoporosis therapies. Parathyroid hormone is an anabolic agent in bone that is more effective in the presence of mature phagocytic macrophages, further supporting the hypothesis that efferocytic macrophages are positive contributors to bone turnover. Therapies which alter macrophage plasticity in tissues other than bone should be explored for their potential to treat bone loss either alone or in conjunction with current bone therapeutics. A better understanding of the exact mechanisms by which macrophages mediate bone homeostasis will lead to an expansion of pharmacologic targets for the treatment of osteoporosis and inflammation-induced bone loss.
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http://dx.doi.org/10.1016/j.pharmthera.2017.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429177PMC
June 2017

Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

J Clin Densitom 2017 Jan - Mar;20(1):8-24. Epub 2016 Dec 9.

Department of Medicine, Cambridge Biomedical Campus, Cambridge, UK.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.
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http://dx.doi.org/10.1016/j.jocd.2016.09.005DOI Listing
June 2018

Preprogrammed Long-Term Systemic Pulsatile Delivery of Parathyroid Hormone to Strengthen Bone.

Adv Healthc Mater 2017 Feb 8;6(3). Epub 2016 Dec 8.

Macromolecular Science and Engineering Center, University of Michigan, Ann Arbor, MI, 48109, USA.

Parathyroid hormone (PTH) is the only US Food and Drug Administration (FDA)-approved anabolic agent for the treatment of osteoporosis. The anabolic action of PTH depends on the mode of PTH administration. Pulsatile administration promotes bone formation, however continuous PTH exposure results in bone resorption. In addition, the therapeutic effect of PTH is optimal when the dose and duration fit the therapeutic window. Current PTH treatment requires daily injection, which is neither a convenient nor a favorable choice of patients. Here, an implantable and biodegradable device capable of long-term pulsatile delivery of PTH is developed as a patient-friendly alternative. The advanced materials and fabrication techniques developed in this work enable us to preprogram a pulsatile delivery device to systemically deliver 21 daily pulses of PTH that build bone in vivo. In addition, the device is biodegradable and absorbable in vivo so that no retraction procedure is needed. Therefore, this implantable and biodegradable pulsatile device holds promise to promote bone growth and treat various conditions of bone loss without the burden of daily injections or secondary surgeries.
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http://dx.doi.org/10.1002/adhm.201600901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299037PMC
February 2017

Local pulsatile PTH delivery regenerates bone defects via enhanced bone remodeling in a cell-free scaffold.

Biomaterials 2017 01 1;114:1-9. Epub 2016 Nov 1.

Macromolecular Science and Engineering Center, University of Michigan, Ann Arbor, MI 48109-1078, USA; Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109-1078, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-1078, USA; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109-1078, USA. Electronic address:

Parathyroid hormone (PTH) is currently the only FDA-approved anabolic drug to treat osteoporosis, and is systemically administered through daily injections. A new local pulsatile PTH delivery device was developed from biodegradable polymers to expand the application of PTH from systemic treatment to spatially controlled local bone defect regeneration in this work. This is the first time that local pulsatile PTH delivery has been demonstrated to promote bone regeneration via enhanced bone remodeling. The biodegradable delivery device was designed to locally deliver PTH in a preprogrammed pulsatile manner. The PTH delivery was utilized to facilitate the regeneration of a bone defect spatially defined with a cell-free biomimetic nanofibrous (NF) scaffold. The local pulsatile PTH delivery (daily pulse for 21 days) not only promoted the regeneration of a critical-sized bone defect with negligible systemic side effects in a mouse model, but also advantageously achieved higher quality regenerated bone than the standard systemic PTH injection. These results demonstrate a promising and novel pulsatile PTH delivery device for spatially defined local bone regeneration.
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http://dx.doi.org/10.1016/j.biomaterials.2016.10.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125900PMC
January 2017

Osteoporosis and Periodontitis.

Curr Osteoporos Rep 2016 12;14(6):284-291

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1101 N. University, Ann Arbor, MI, 48109-1078, USA.

Osteoporosis and periodontitis are both diseases characterized by bone resorption. Osteoporosis features systemic degenerative bone loss that leads to loss of skeletal cancellous microstructure and subsequent fracture, whereas periodontitis involves local inflammatory bone loss, following an infectious breach of the alveolar cortical bone, and it may result in tooth loss. Most cross-sectional studies have confirmed the association of osteoporosis and periodontitis primarily on radiographic measurements and to a lesser degree on clinical parameters. Multiple shared risk factors include age, genetics, hormonal change, smoking, as well as calcium and vitamin D deficiency. Both diseases could also be risk factors for each other and have a mutual impact that requires concomitant management. Suggested mechanisms underlying the linkage are disruption of the homeostasis concerning bone remodeling, hormonal balance, and inflammation resolution. A mutual interventional approach is emerging with complex treatment interactions. Prevention and management of both diseases require interdisciplinary approaches and warrants future well-controlled longitudinal and interventional studies for evidence-based clinical guidelines.
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http://dx.doi.org/10.1007/s11914-016-0330-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654540PMC
December 2016

Modulation of Osteoblastic Cell Efferocytosis by Bone Marrow Macrophages.

J Cell Biochem 2016 12 5;117(12):2697-2706. Epub 2016 May 5.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, 48109.

Apoptosis occurs at an extraordinary rate in the human body and the effective clearance of dead cells (efferocytosis) is necessary to maintain homeostasis and promote healing, yet the contribution and impact of this process in bone is unclear. Bone formation requires that bone marrow stromal cells (BMSCs) differentiate into osteoblasts which direct matrix formation and either become osteocytes, bone lining cells, or undergo apoptosis. A series of experiments were performed to identify the regulators and consequences of macrophage efferocytosis of apoptotic BMSCs (apBMSCs). Bone marrow derived macrophages treated with the anti-inflammatory cytokine interleukin-10 (IL-10) exhibited increased efferocytosis of apBMSCs compared to vehicle treated macrophages. Additionally, IL-10 increased anti-inflammatory M2-like macrophages (CD206 ), and further enhanced efferocytosis within the CD206 population. Stattic, an inhibitor of STAT3 phosphorylation, reduced the IL-10-mediated shift in M2 macrophage polarization and diminished IL-10-directed efferocytosis of apBMSCs by macrophages implicating the STAT3 signaling pathway. Cell culture supernatants and RNA from macrophages co-cultured with apoptotic bone cells showed increased secretion of monocyte chemotactic protein 1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) and transforming growth factor beta 1 (TGF-β1) and increased ccl2 gene expression. In conclusion, IL-10 increases M2 macrophage polarization and enhances macrophage-mediated engulfment of apBMSCs in a STAT3 phosphorylation-dependent manner. After engulfment of apoptotic bone cells, macrophages secrete TGF-β1 and MCP-1/CCL2, factors which fuel the remodeling process. A better understanding of the role of macrophage efferocytosis as it relates to normal and abnormal bone turnover will provide vital information for future therapeutic approaches to treat bone related diseases. J. Cell. Biochem. 117: 2697-2706, 2016. © 2016 Wiley Periodicals, Inc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055427PMC
http://dx.doi.org/10.1002/jcb.25567DOI Listing
December 2016

Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone.

J Cell Biochem 2016 07 19;117(7):1556-67. Epub 2016 Feb 19.

Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan.

Anabolic actions of PTH in bone involve increased deposition of mineralizing matrix. Regulatory feedback of the process may be important to maintain calcium homeostasis and, in turn, calcium may inform the process. This investigation clarified the role of calcium availability and the calcium sensing receptor (CaSR) in the anabolic actions of PTH. CaSR function promoted osteoblastic cell numbers, with lower cell numbers in post-confluent cultures of primary calvarial cells from Col1-CaSR knock-out (KO) mice, and for calvarial cells from wild-type (WT) mice treated with a calcilytic. Increased apoptosis of calvarial cells with calcilytic treatment suggested CaSR is critical for protection against stage-dependent cell death. Whole and cortical, but not trabecular, bone parameters were significantly lower in Col1-CaSR KO mice versus WT littermates. Intact Col1-CaSR KO mice had lower serum P1NP levels relative to WT. PTH treatment displayed anabolic actions in WT and, to a lesser degree, KO mice, and rescued the lower P1NP levels in KO mice. Furthermore, PTH effects on whole tibiae were inhibited by osteoblast-specific CaSR ablation. Vertebral body implants (vossicles) from untreated Col1-CaSR KO and WT mice had similar bone volumes after 4 weeks of implantation in athymic mice. These findings suggest that trabecular bone formation can occur independently of the CaSR, and that the CaSR plays a collaborative role in the PTH anabolic effects on bone. J. Cell. Biochem. 117: 1556-1567, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856537PMC
July 2016

Juxtacrine interaction of macrophages and bone marrow stromal cells induce interleukin-6 signals and promote cell migration.

Bone Res 2015 16;3:15014. Epub 2015 Jun 16.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry , Ann Arbor, MI 48109, USA ; Department of Pathology, University of Michigan Medical School , Ann Arbor, MI 48109, USA.

The bone marrow contains a heterogeneous milieu of cells, including macrophages, which are key cellular mediators for resolving infection and inflammation. Macrophages are most well known for their ability to phagocytose foreign bodies or apoptotic cells to maintain homeostasis; however, little is known about their function in the bone microenvironment. In the current study, we investigated the in vitro interaction of murine macrophages and bone marrow stromal cells (BMSCs), with focus on the juxtacrine induction of IL-6 signaling and the resultant effect on BMSC migration and growth. The juxtacrine interaction of primary mouse macrophages and BMSCs activated IL-6 signaling in the co-cultures, which subsequently enhanced BMSC migration and increased BMSC numbers. BMSCs and macrophages harvested from IL-6 knockout mice revealed that IL-6 signaling was essential for enhancement of BMSC migration and increased BMSC numbers via juxtacrine interactions. BMSCs were the main contributor of IL-6 signaling, and hence activation of the IL-6/gp130/STAT3 pathway. Meanwhile, macrophage derived IL-6 remained important for the overall production of IL-6 protein in the co-cultures. Taken together, these findings show the function of macrophages as co-inducers of migration and growth of BMSCs, which could directly influence bone formation and turnover.
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http://dx.doi.org/10.1038/boneres.2015.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637844PMC
November 2015

Macrophages: Their Emerging Roles in Bone.

J Bone Miner Res 2015 Dec;30(12):2140-9

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health.
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http://dx.doi.org/10.1002/jbmr.2735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876707PMC
December 2015

Bone marrow macrophages support prostate cancer growth in bone.

Oncotarget 2015 Nov;6(34):35782-96

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.
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http://dx.doi.org/10.18632/oncotarget.6042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742141PMC
November 2015

Inflammation and skeletal metastasis.

Bonekey Rep 2015 10;4:706. Epub 2015 Jun 10.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry , Ann Arbor, MI, USA ; Department of Pathology, University of Michigan Medical School , Ann Arbor, MI, USA.

On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.
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http://dx.doi.org/10.1038/bonekey.2015.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461889PMC
July 2015

Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.

J Bone Miner Res 2015 Jan;30(1):3-23

This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.
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http://dx.doi.org/10.1002/jbmr.2405DOI Listing
January 2015

U-M School of Dentistry: an amazing year!

J Mich Dent Assoc 2014 Sep;96(9):34-7, 74

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September 2014

Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells.

Stem Cells 2014 Nov;32(11):2845-57

Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

Head and neck squamous cell carcinomas (HNSCC) contain a small subpopulation of stem cells endowed with unique capacity to generate tumors. These cancer stem cells (CSC) are localized in perivascular niches and rely on crosstalk with endothelial cells for survival and self-renewal, but the mechanisms involved are unknown. Here, we report that stromal interleukin (IL)-6 defines the tumorigenic capacity of CSC sorted from primary human HNSCC and transplanted into mice. In search for the cellular source of Interleukin-6 (IL-6), we observed a direct correlation between IL-6 levels in tumor-associated endothelial cells and the tumorigenicity of CSC. In vitro, endothelial cell-IL-6 enhanced orosphere formation, p-STAT3 activation, survival, and self-renewal of human CSC. Notably, a humanized anti-IL-6R antibody (tocilizumab) inhibited primary human CSC-mediated tumor initiation. Collectively, these data demonstrate that endothelial cell-secreted IL-6 defines the tumorigenic potential of CSC, and suggest that HNSCC patients might benefit from therapeutic inhibition of IL-6/IL-6R signaling.
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http://dx.doi.org/10.1002/stem.1793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198458PMC
November 2014

Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis.

J Biol Chem 2014 Aug 8;289(35):24560-72. Epub 2014 Jul 8.

From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109,

Tumor cells secrete factors that modulate macrophage activation and polarization into M2 type tumor-associated macrophages, which promote tumor growth, progression, and metastasis. The mechanisms that mediate this polarization are not clear. Macrophages are phagocytic cells that participate in the clearance of apoptotic cells, a process known as efferocytosis. Milk fat globule- EGF factor 8 (MFG-E8) is a bridge protein that facilitates efferocytosis and is associated with suppression of proinflammatory responses. This study investigated the hypothesis that MFG-E8-mediated efferocytosis promotes M2 polarization. Tissue and serum exosomes from prostate cancer patients presented higher levels of MFG-E8 compared with controls, a novel finding in human prostate cancer. Coculture of macrophages with apoptotic cancer cells increased efferocytosis, elevated MFG-E8 protein expression levels, and induced macrophage polarization into an alternatively activated M2 phenotype. Administration of antibody against MFG-E8 significantly attenuated the increase in M2 polarization. Inhibition of STAT3 phosphorylation using the inhibitor Stattic decreased efferocytosis and M2 macrophage polarization in vitro, with a correlating increase in SOCS3 protein expression. Moreover, MFG-E8 knockdown tumor cells cultured with wild-type or MFG-E8-deficient macrophages resulted in increased SOCS3 expression with decreased STAT3 activation. This suggests that SOCS3 and phospho-STAT3 act in an inversely dependent manner when stimulated by MFG-E8 and efferocytosis. These results uncover a unique role of efferocytosis via MFG-E8 as a mechanism for macrophage polarization into tumor-promoting M2 cells.
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http://dx.doi.org/10.1074/jbc.M114.571620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148880PMC
August 2014

Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2.

J Immunol 2014 Jul 2;193(1):26-9. Epub 2014 Jun 2.

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115.

Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by poorly defined mechanisms. Specialized proresolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution, but little is known regarding this process in the bone marrow. In this study, metabololipidomic profiling via liquid chromatography mass spectrometry revealed higher levels of specialized proresolving mediators in the bone marrow relative to the spleen. The endocrine and bone anabolic agent parathyroid hormone increased specialized proresolving mediator levels, including resolvins (Rvs), in bone marrow. Human and murine primary macrophages efferocytosed apoptotic osteoblasts in vitro, and RvD1 and RvD2 (10 pM-10 nM) enhanced this process. These findings support a unique profile of specialized lipid mediators in bone marrow that contribute to a feedback system for resolution of inflammation and maintenance of skeletal homeostasis.
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http://dx.doi.org/10.4049/jimmunol.1301945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285693PMC
July 2014

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.

Proc Natl Acad Sci U S A 2014 Jan 9;111(4):1545-50. Epub 2014 Jan 9.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109.

Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms(+) myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68(+) cells, whereas clodronate liposome-treated mice had increased CD68(+) and CD163(+) cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.
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http://dx.doi.org/10.1073/pnas.1315153111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910564PMC
January 2014