Dr. Cliff Rosen

For Media Inquiries:  Contact Caroline Cornish, Maine Medical Center Communications & Public Affairs Manager, 207-662-5146

Clifford J. Rosen, MD

Faculty Scientist
Director, Center for Clinical & Translational Research
Dr. Rosen is one of the lead Principal Investigators of
the Northern New England CTR Network

Education
BS: Biochemistry, University of Maine, Orono, Maine
MD: State University of New York at Syracuse, Syracuse, NY

The central theme of the Rosen laboratory is understanding the metabolic and biochemical fate of marrow stromal cells as progenitor osteoblasts and/or adipocytes. In vivo, this translates into defining the relationship between marrow adipogenesis and osteoblastogenesis, and the interactions between whole body and skeletal metabolism. We use age, genetic, environmental, diet, and pharmacologic manipulations in order to understand the complex regulation of bone remodeling. We use a variety of techniques to address our research questions, including DXA imaging, NMR, microCT, MRI, osmium tetroxide staining, histomorphometry, immunohistochemistry, immunofluorescence, confocal microscopy, Seahorse extracellular flux analysis, and metabolic in vivo studies using Promethion technology.

The lab has strong collaborative work with internal and external laboratories and hospitals world wide involving sophisticated primary culturing of osteoblast, osteoclasts, osteocytes, and adipocytes. We currently collaborate with the Spiegelman Laboratory at the Dana Farber Cancer Institute studying the role of irisin in bone remodeling. Dr. Eben Estell in our lab heads up the Maine part of the collaboration, and he has been studying the effects of irisin on osteoclasts. We combine our in vivo observations with in vitro cell culture models in order to understand the mechanisms through which those binding proteins act.

Additionally, our lab is also interested in understanding the in vivo roles of IGF binding proteins (IGFBP) namely IGFBP2 in defining osteoblast and osteoclast function. Our laboratory uses global and conditional knockout murine models to understand the effects of the IGFBP regulatory system on bone modeling and remodeling and fat acquisition. This includes studies of wildtype and Igfbp-2 null mice before and after vertical sleeve gastrectomy leads by Dr. Alison Pletch.

Rosen_Fig1

Fig 1: Fluorescence microscopy of murine preosteoblasts.

Rosen_Fig2

Fig 2: Three-dimensional microCT of the distal femur trabecular bone.

Rosen_Fig3

Fig 3: MicroCT image of osmium-tetroxide stained marrow adipose tissue.

Fig 4: Goldner’s Trichrome stained of a femur

Fig 5: Trabeculae were labeled with calcein and alizarin red

Fig 7: Calcein stained calvarial organ culture.

Fig 6: Calcein stained calvarial organ culture.

Fig 7: TRAP stained osteoclasts

Fig 8: H&E stained of femur marrow compartment with white adipocyte ghosts.

Fig 9: Lipid droplets in adipocytes of an in vitro culture from bone marrow stromal cells

Fig 10: Oil Red O stained lipid droplets in adipocytes generated from bone marrow stromal cells

Bornstein_Sheilia_TSheila Bornstein, MS

Scientific Manager
bornss@mmc.org

Research Interests: Sheila has been instrumental in studies related to the interplay of bone and fat under different conditions such as lactation, high fat diet, calorie restriction and cold exposure. Previously, we reported that metabolic changes during lactation of C57BL/6J mice were due in part to increased circulating FGF-21, which in turn could accentuate bone loss. Sheila has also been instrumental in organizing experimental protocols with Dr. Rosen’s team for submission to the IACUC at MMCRI.  Currently Sheila is transitioning to clinical work after obtaining her nursing degree. She is currently working with high-risk pregnancy patients at the prenatal center at MMC while supporting the Rosen lab with IACUC protocol preparation part time.

Victoria DeMambro, MS

Scientific Manager (pictured left)
demamv@mmc.org

Research Interests: Manager of Physiology Core Facility

Jennifer Daruszka, B.S

Research Assistant II (pictured right)

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More than 100 million individuals worldwide have osteoporosis with both men and women losing bone as they get older. In females, there is a phase of accelerated bone loss that occurs prior to menopause coupled with the beginnings of visceral adiposity, energy imbalances and reductions in physical activity as well as rising follicle stimulating hormone (FSH) levels but normal estrogen levels. Indeed, strong correlations have been found between perimenopausal serum FSH levels and bone loss in human epidemiology studies.

Recently in collaboration with researchers at Mount Sinai, the Rosen Lab has investigated the role of FSH in post-menopausal bone loss and weight gain utilizing an antibody to the b-subunit of FSH (a-FSH). The project led by Ms. DeMambro has previously shown (Nature, 2017) that treatment with the a-FSH antibody protects against ovariectomy induced bone loss, weight gain and marrow adiposity. Interestingly, increases in white fat beiging and thermogenesis with treatment were noted. Aging studies funded by the NIA are ongoing with assistance from Research Assistant Jennifer Daruszka, BS, to investigate whether the a-FSH antibody can reduced whole body fat mass and marrow adiposity while simultaneously increasing bone mass in aging populations of mice. There is significant translational potential of these findings for the prevention and treatment of disease in aging human populations.

In addition, Victoria DeMambro manages the Physiology Core here at MMCRI with assistance from Jennifer Daruszka. The Physiology Core is based out of the Rosen Lab, specializing in in vivo and in vitro metabolic phenotyping for institutional PI’s as well as outside investigators.

Eben G. Estell, PhD

Postdoctoral Fellow
eestell@mmc.org

In collaboration with the Spiegelman Lab at Dana Farber Cancer Institute, postdoctoral fellow Eben Estell is examining the role of irisin in mediating muscle-bone crosstalk during exercise. He is conducting research on the action of the protein irisin on cells in the bone remodeling unit. Irisin was first characterized in the Spiegelman Lab as a myokine, or muscle-derived signaling factor, that is acutely elevated in response to exercise and able to potently modulate thermogenesis in adipose tissue. Recently an impact on bone homeostasis has been demonstrated, but it is currently unclear the effects of irisin in this regard as purely anabolic or comprise a more complex regulation of coupled remodeling. In the Rosen Lab, we are currently investigating the effect of irisin signaling on osteoclasts, the bone-resorbing cell of the remodeling unit. We hypothesize that this novel myokine can directly stimulate osteoclast differentiation and bone resorption and anticipate this work will further elucidate the complete picture of irisin’s impact on skeletal homeostasis, as well as its potential therapeutic application in protecting against bone loss.

Irisin treatment increases osteoclast differentiation. TRAP-positive stained osteoclasts (red) in untreated (control) and 10 ng/mL irisin treated conditions after 7 days of growth factor-stimulated differentiation from bone marrow-derived precursors (imaged at 10X magnification).

Benjamin Harris, MS

Medical Student at the University of New England

Benjamin Harris is continuing work examining the physiologic mechanisms behind bone loss after bariatric surgery. Specifically, he is currently investigating the role of insulin-like growth factor binding protein 2 (IGFBP2) in bone metabolism status post vertical sleeve gastrectomy in IGFBP2 knockout and wild type mice. Another focus of Ben’s work regarding bone loss after bariatric surgery is characterizing the inflammatory mediators in post-operative mice. Groups of CD45+, F4/80+, and CD11b+ macrophages, known as osteomacs, are of interest and known to be associated with bone loss. He is working to identify levels of resistin, adiponectin, plexinD1, TNF and RCAN2 after the surgery as well.

Figueroa_Carolina_TCarolina Figueroa, MS

Doctoral Candidate
CFigueroa@mmc.org

Carolina is interested in the implications of α-synuclein aggregates, hallmark of Parkinson’s disease (PD), in comorbidities related to body composition. PD patients often present low bone mineral density (BMD) and body mass index (BMI), are at high risk of fracture and fall frequently due to locomotor dysfunction. To better understand α-synuclein role in bone and adipose tissue homeostasis, Ms. Figueroa is currently studying the effects deletion and overexpression of α-synuclein have in estrogen deficiency induced-bone loss and diet-induced obesity mouse models.

Le_Phuong_TPhuong Le, MS

Scientific Manager II
lep@mmc.org

 Research Interests: Besides managing day-to-day operations of Dr. Rosen’s lab, my research work has been examining the role of Zinc finger protein 467 (Zfp467) in bone and fat. Zfp467 is implicated as a novel regulator of cell fate by inhibiting osteoblast commitment and stimulating adipocyte differentiation, my study explores the genetic loss of Zfp467 and whether or not Zfp467 knock out (Zfp467-/-) shifts mesenchymal cell fate towards osteogenesis. Additionally, I am also investigating the relationship of bone and fat in Zfp467-/- under high fat diet challenge, as we know diet induced obesity has become a major health concern resulting in increased skeletal fragility and impaired bone turnover. Bone loss has been observed in many high fat diet studies suggesting an important connection between adipose tissue and bone remodeling. Therefore, my work is to determine if genetic loss of Zfp467 protects mice from diet induced obesity and bone loss. Furthermore, my research focus is to also determine if in fact Zfp467-/- mice are protected against bone loss in an estrogen deficiency condition using an ovariectomy model.

Isabella Leon Calle, B.A

Master’s Candidate

Isabella Leon Calle has been investigating the Zinc Finger Protein 467 (Zfp467) gene and its role in mediating the effects of parathyroid hormone (PTH). Using a Zfp467 global knock out (KO) mouse model, Ms. Leon Calle has been working with Hanghang Liu to isolate calvarial osteoblasts and bone marrow stromal cells, grow them in-vitro, and expose them to varying doses and durations of PTH treatment. Together with these methods and several others (i.e. stainings, qPCR, western blot, metabolism studies, and cAMP assays), we demonstrated that Zfp467 KO mice enhanced the anti-adipogenic, pro-osteogenic effects of PTH. The KO cells appear to have an increased sensitivity to PTH, as compared to WT. Because many of the pharmacological agents for osteoporosis are PTH analogues, these findings could have significant clinical implications for millions of patients suffering from osteoporosis worldwide. This in-vitro project was done for Ms. Leon Calle’s Master’s thesis. She is working towards applying to medical school in the coming year and plans to continue researching.

Hanghang Liu, MS

Visiting Scholar and Doctoral Candidate

Hanghang Liu came to us from the West China Hospital of Stomatology, Sichuan University, China. He is interested in understanding how Zfp467 plays a role in mediating the anti-adipogenic and pro-osteogenic effects of parathyroid hormone. In our lab, Mr. Liu has used the calvarial osteoblast (COB) and bone marrow stromal cells (BMSCs) from Zfp467 wild type and knockout mice to study the exact mechanism how Zfp467 regulate osteogenesis, adipogenesis and cellular respiration.

Gisela PachonGisela Pachon, PhD

Postdoctoral Research Fellow

OPachonPen@mmc.org

I am currently developing new projects related to components of the immune response that drive inflammation and accelerate bone loss in aged mice.   I found evidence from a ‘first in kind’ clinical trial that macrophage activation in marrow may be an important initiating component during expansion of adipocytes. We use a mouse model of enhanced sensitivity to a high fat diet (i.e. the congenic 6T strain) to confirm a marrow inflammatory response. In the former, I showed that a marker of macrophage activation and TLR4 signaling, resistin, are markedly increased in marrow sera but not in the circulation from normal individuals after a short period of high-fat diet, and not after fasting. My current work focuses on understanding the immune response in the context of marrow adiposity in mouse models. Characterization of how inflammation contributes to the pathogenesis of age-related bone loss, as well as, defining the inflammatory cell population and understanding their function in the marrow niche as marrow adipocytes expand in aging mice will be a principal focus of my research.

Alison Pletch, MD

Surgical Resident

Alison is a surgical resident spending a year with us conducting research on IGFBP2 in mice who have undergone sleeve gastrectomies. Sustained and progressive bone loss has been observed in human patients who have undergone bariatric surgery. The underlying mechanism is not well understood. Previously, we have reported that IGFBP2 is essential for osteoclast proliferation and differentiation. In humans, IGFBP2 has been shown to be the most highly expressed protein in the serum after sleeve gastrectomies. Dr. Pletch’s project aims to explore the connection between IGFBP2 in post-gastrectomy mice and the bone loss observed.

A complete list of publications can be found on My NCBI

Rosen CJ, Ingelfinger JR. Unraveling the Function of FTO Variants. The New England journal of medicine. 2015; 373(10):964-5. PubMed [journal] PMID: 26287747

Fazeli PK, Faje AT, Cross EJ, Lee H, Rosen CJ, et al. Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa. Bone. 2015; 77:6-11. NIHMSID: NIHMS680372 PubMed [journal] PMID: 25868802, PMCID: PMC4447546

Sharma A, Flom PL, Rosen CJ, Schoenbaum EE. Racial differences in bone loss and relation to menopause among HIV-infected and uninfected women. Bone. 2015; 77:24-30. NIHMSID: NIHMS682538 PubMed [journal] PMID: 25896953, PMCID: PMC4418198

Lecka-Czernik B, Rosen CJ. Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015; 30(8):1356-61. PubMed [journal] PMID: 26094610

Lecka-Czernik B, Rosen CJ. Skeletal integration of energy homeostasis: Translational implications. Bone. 2015; PubMed [journal] PMID: 26211994

Motyl KJ, DeMambro VE, Barlow D, Olshan D, Nagano K, et al. Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice. Endocrinology. 2015; 156(7):2374-83. PubMed [journal] PMID: 25853667, PMCID:
PMC4475716

Taylor CL, Thomas PR, Aloia JF, Millard PS, Rosen CJ. Questions About Vitamin D
for Primary Care Practice: Input From an NIH Conference. The American journal of
medicine. 2015; PubMed [journal] PMID: 26071820

Reagan MR, Liaw L, Rosen CJ, Ghobrial IM. Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast. Bone. 2015; 75:161-9. PubMed [journal] PMID: 25725265

Swanson CM, Shea SA, Stone KL, Cauley JA, Rosen CJ, et al. Obstructive sleep apnea and metabolic bone disease: insights into the relationship between bone and sleep. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015; 30(2):199-211. PubMed [journal] PMID: 25639209

Devlin MJ, Rosen CJ. The bone-fat interface: basic and clinical implications of marrow adiposity. The lancet. Diabetes & endocrinology. 2015; 3(2):141-7. NIHMSID: NIHMS603820 PubMed [journal] PMID: 24731667, PMCID: PMC4138282

Editorial Boards

  • 1992-2002: Editorial Board, Journal of Bone and Mineral Research
  • 1995-1999: Editorial Board, Journal of Clinical Endocrinology and Metabolism
  • 1997-2002: Editor in Chief, Journal of Clinical Densitometry
  • 2003-2007: Associate Editor, Journal Bone and Mineral Research
  • 2003-2008:Editorial Board, Endocrinology
  • 2006-Present: Editor in Chief, Primer on Metabolic Diseases, ASBMR
  • 2009-2014: Associate Editor, Journal of Clinical Endocrinology and Metabolism
  • 2010-2015: Associate Editor- Aging Cell
  • 2013-Present: Senior Associate Editor- Journal of Bone and Mineral Research
  • 2014- Present: Associate Editor- New England Journal of Medicine
  • 2015- Present: Associate Editor- Endocrine Reviews

Professional Activities

  • 1988-Present: Member, The Endocrine Society, Bethesda, MD
  • 1989-Present: Member, American Society of Bone and Mineral Research
  • 1994-Present: Member, American Academy for the Advancement of Science
  • 1995-Present: Member, New York Academy of Sciences
  • 1996-2002: Member, Scientific Advisory Board, National Osteoporosis Foundation
  • 1997-2001: Chair, NIH/NICHD Peer-Review Study Section “RFA: Peak Bone Mass”
  • 1999-2002: Permanent Member, NIH Peer Review Group, OBM-2
  • 2002-2003: President, American Society for Bone and Mineral Research
  • 2002-2004: Chair, NIH Peer Review Group, OBM-2
  • 2006-Present: Member, FDA Endocrinology and Metabolism Advisory Board
  • 2007-2010: Member, NIH/NIAMS Advisory Council
  • 2008-2011: Member, NIA Clinical Trials Advisory Board
  • 2009-Present: Institute of Medicine Committee Member, Calcium and Vitamin D
  • 2012-Present: Institute of Medicine Committee Member- Review of the NIH CTSA Program
  • 2011-Present: American Board of Internal Medicine-Endocrinology and Metabolism Panel of Experts