Rob Blank is Professor of Medicine of the Division of Endocrinology and Molecular Medicine. He holds secondary appointments in the departments of Cell Biology, Neurobiology and Anatomy and Physiology. He is Director of the TOPS Obesity Center and a trainer in the Interdisciplinary Program in Biomedical Sciences. He holds undergraduate degrees from Columbia University (history and philosophy of science) and the University of Cambridge (genetics). He earned his MD and PhD (basic medical sciences/biochemistry) degrees at New York University and trained in internal medicine at New York Presbyterian Hospital/Weill Cornell. He remained at Weill Cornell and Memorial Sloan-Kettering Cancer Center for an endocrinology fellowship. He was a postdoctoral fellow at Rockefeller University. On completing his training, he remained at the tri-institutional campus as a faculty member at the Hospital for Special Surgery and the Weill-Cornell College of Medicine before moving to the University of Wisconsin in 2000. He remained there until 2013, when he joined the Medical College of Wisconsin faculty.
Dr. Blank's laboratory studies the genetics of bone biomechanical performance and of vertebral development, primarily in mice. We are particularly interested in understanding the relationship among different aspects of biomechanical performance and the mechanisms underlying pleiotropy of bone quantitative trait loci. We are currently studying a quantitative trait locus that affects multiple aspects of bone size and shape, whose pleiotropy extends to include important cardiovascular and reproductive phenotypes. Fully understanding the underlying biology is a prominent goal of our present work. We are also interested in understanding the genetic basis of congenital vertebral malformations and idiopathic scoliosis.
Dr. Blank is actively engaged in education. He is a trainer in the Interdisciplinary Program in Biomedical Sciences. He is also a trainer in the University of Wisconsin's Endocrinology and Reproductive Physiology training program, and is thesis advisor to 2 PhD students in the program. He is the author of several articles on educational topics.
In the clinic, Dr. Blank focuses on metabolic bone disease, disorders of mineral metabolism, and genetic endocrine diseases. Because his clinical practice includes many patients with parathyroid disease and with developmental anomalies of the skeleton, Dr. Blank works closely with the Endocrine Surgery Program and the Genetic Counseling Program, both of which are hosted by the Cancer Center.
Selected CollaboratorsNeil Binkley
Selected Professional Societies
Advances in Mineral Metabolism
American Society for Bone and Mineral Research
American Society of Human Genetics
Complex Trait Community
Genetics Society of America
International Consortium for Vertebral Anomalies and Scoliosis
International Society for Clinical Densitometry
The Endocrine Society
Dr. Blank staffs endocrinology clinics at the Clement J Zablocki VAMC. These clinics serve as an important educational venue for endocrinology fellows and internal medicine residents.
Dr. Blank also maintains a focused endocrinology practice at the Froedtert Hospital Metabolic Bone Disease and Mineral Metabolism Program. This clinic is devoted to particularly challenging metabolic bone and mineral disorders and on genetic endocrine disorders. This clinic is also a teaching venue for residents and fellows.
He remains a member of the University of Wisconsin Osteoporosis Clinical Center and Research Program. This center conducts clinical research on bone diseases, methods for their diagnosis, and sponsored trials of drugs used for their treatment. Karen Hansen, Bjoern Buehring, and Neil Binkley are key collaborators. On the Medical College of Wisconsin Campus, Dr. Blank conducts human studies through the Clinical and Translational Science Institute.
MD and PhD, New York University, New York, NY, 1988
BA, University of Cambridge, Cambridge, UK, 1980
AB, Columbia University, New York, NY, 1978
Dr. Blank’s laboratory studies the genetics of bone biomechanical performance and of vertebral development, primarily in mice. We are particularly interested in understanding the relationship among different aspects of biomechanical performance and the mechanisms underlying pleiotropy of bone quantitative trait loci. We are currently studying a quantitative trait locus that affects multiple aspects of bone size and shape, whose pleiotropy extends to include important cardiovascular and reproductive phenotypes. Fully understanding the underlying biology is a prominent goal of our present work. We are also interested in understanding the genetic basis of congenital vertebral malformations and idiopathic scoliosis.
Over two million low trauma fractures occur annually in the US. A woman's lifetime low trauma fracture risk approaches 50%, and one year mortality following hip fracture approaches 25%. Low trauma fractures are therefore a leading cause of morbidity, mortality, and health care spending.
The Blank lab has a long-standing interest in the genetic basis of variation in bone's biomechanical performance. 3-point bending tests, along with supporting imaging, biochemistry, genotyping, and gene expression data allow us to obtain a comprehensive understanding of what makes bones differ in how hard they are to break. A key concept is that there are multiple aspects of biomechanical performance; they are all important and each is distinct from the others. Stiffness is a measure of how much a bone deforms in response to applied force or load. Strength is a measure of how much force a bone can absorb before fracturing. Ductility (the opposite of brittleness) is a measure of how much a bone will bend before it fractures. All of these can be measured in the 3-point bending test. Ultimately, three different domains determine a bone's mechanical behavior – the detailed composition of its tissue, its size, and its shape.
Approximately 70% of the variation in bone properties can be attributed to genetics. We have used the general approach described above to map quantitative trait loci (QTLs) for bone biomechanical performance and construct new congenic mouse strains in which these have been isolated. Many medically important traits, including fracture susceptibility are controlled by multiple, interacting genes as well as the environment. By relating trait values to genotype, it is possible to detect the contributions of chromosome regions and specific genes to the trait.
We recently completed a collaborative study with Denise Ney to determine the contributions of genotype and diet to reduced biomechanical performance in a mouse model of phenylketonuria (PKU). We found that the mice with PKU have a global defect in biomechanical performance, regardless of diet. We further found that the amino acid diet used to treat PKU impairs bone growth, while a novel diet attenuates the impact of the restricted diet.
Because of the Blank lab's interest in the integration of the various aspects of biomechanical performance, we have particular interest in the relationships among various bone traits. These clearly display covariation, and the nature of that covariation provides insight into the physiologic mechanisms by which biomechanical performance is achieved and maintained.
Load bearing by the skeleton (e.g. walking, jumping) stimulates bone growth, while unloading (e.g. space flight, prolonged bed rest, paralysis) stimulates bone resorption. Bone is thereby physiologically adapted to its usual loading environment. Bone may also be lost in conditions in which calcium or phosphate balance can't be maintained. When bone is out of balance either nutritionally or mechanically, a response occurs to try and reestablish balance. The details of which mechanisms dominate the response, bone will develop a characteristic size, shape, and tissue-level properties. These details are largely determined by genetic constitution, as illustrated by the mouse strains HcB-8 and HcB-23, which were developed by Peter Demant, MD, PhD.
The covariation of various bone traits causes many of the genes that influence bone biomechanical performance to affect multiple traits, rather than just one. This phenomenon is called pleiotropy. Pleiotropy is illustrated by the genetic linkage map of mouse chromosome 10 shown here, which shows that multiple traits are controlled by a gene in the same region of the chromosome.
Some of the genes affecting bone biomechanics work differently in males and females. This is true in both humans and mice. This linkage map of mouse chromosome 6 illustrates this; there is a pleiotropic gene affecting multiple traits in males, but it has no effect in females.
In collaboration with Narayan Yoganandan, PhD, we are studying how pleiotropic bone genes affect bone growth in response to mechanical loading under reproducible experimental conditions.
Ongoing work with Marc Drezner, MD, seeks to understand the mechanisms that lead to osteomalacia and phosphate wasting in X-linked hypophosphatemia. See his page for additional information about this work.
New projects will look to extend our findings in mice to humans. These clinical efforts will be conducted through the Clinical and Translational Science Institute.
The lines of investigation summarized on this page are part of our effort not just to identify genes that affect bone properties, but to understand how their varied functions are integrated.
Our bone linkage mapping experiments identified a pleiotropic QTL to a small region of chromosome 4. The QTL affected 10 traits related to bone size, shape, and biomechanical performance, but none at the tissue level. In contrast, the QTLs on other chromosomes affect both whole bone and tissue-level properties. This led us to infer that this QTL acts by modulating radial bone growth.
Ece1, the gene encoding endothelin converting enzyme 1, is a positional candidate for this QTL. This gene is essential for neural crest cell migration, induction of the Purkinje system, proper development of the cardiac outflow tract during development, and formation of the mandible. ECE1 protein catalyzes the conversion of biologically inert big endothelin 1 to active endothelin 1(ET1). ET1 is a small peptide hormone that mediates blood pressure in a paracrine fashion.
Hypothesizing that if Ece1 is the gene underlying the chromosome 4 QTL, we reasoned that this might result in pleiotropy extending to vascular phenotypes. We undertook initial studies in collaboration with Naomi Chesler to explore this possibility. We found that HcB-23 mice have larger, more easily stretched arteries than HcB-8 mice, paralleling the differences observed between bones in these strains.
In addition, we have observed that HcB-8 mice have larger hearts, smaller litters, and lower expression of Ece1 and its downstream target, Nos3, in multiple tissues.
We have developed a conditional knockout allele of Ece1. Global Ece1 knockout mice have multiple abnormal phenotypes and are not viable. We are therefore using the conditional knockout to study the bone, vascular, and reproductive phenotypes that differ between HcB-8 and HcB-23 mice. These studies are being done in collaboration with Julian Lombard, PhD, Naomi Chesler, Ron Magness, PhD, and Rashmi Sood, PhD. Work on this project is critically dependent on the Cardiovascular Center.
Scoliosis is an abnormal lateral curvature of the vertebral column. Most cases are idiopathic, meaning that no cause for the curvature is known. Idiopathic scoliosis is relatively common, with about 5% of post-pubertal females having curves exceeding 10%. Congenital vertebral malformations are much less common, and cause scoliosis because the vertebral bodies themselves are misshapen. Unlike the case in idiopathic scoliosis, the contributions of several genes to congenital vertebral malformations are known. However, what we know is much less than what remains to be learned.
The Blank lab has a long-standing collaboration with Drs. Phil Giampietro and Cathy Raggio to study the genetic basis of scoliosis and congenital vertebral malformations. Additional key participants in this work include Uli Broeckel, MD and Mike Pickart. The collaborative network is expanding through the International Consortium for Vertebral Anomalies and Scoliosis, established to allow investigators to pool data and expertise world-wide. We have reported linkage of idiopathic scoliosis to chromosome 12p and detection of a potentially pathogenic mutation in T, an essential gene for vertebral patterning, in patients with diverse vertebral malformations.
Jasmin Kristianto (PhD student, UW-Madison Endocrinology and Reproductive Physiology Program)
Michael Johnson (PhD student, UW-Madison Endocrinology and Reproductive Physiology Program)
Zhaohu Wang (Technician)
(Bialkowski W, Blank RD, Zheng C, Gottschall JL, Papanek PE.) Bone Rep. 2019 Jun;10:100188.
(Carey JJ, Lewiecki EM, Blank RD, Shuhart CR, Buehring B.) Ann Intern Med. 2017 Dec 19;167(12):901.
(Silberberg SD, Crawford DC, Finkelstein R, Koroshetz WJ, Blank RD, Freeze HH, Garrison HH, Seger YR.) Nature. 2017 08 09;548(7666):153-154.
(Binkley N, Blank RD, Leslie WD, Lewiecki EM, Eisman JA, Bilezikian JP.) J Bone Miner Res. 2017 Jul;32(7):1391-1394.
(Kristianto J, Johnson MG, Zastrow RK, Radcliff AB, Blank RD.) Transgenic Res. 2017 06;26(3):411-417.
(Johnson MG, Konicke K, Kristianto J, Gustavson A, Garbo R, Wang X, Yuan B, Blank RD.) Physiol Rep. 2017 Feb;5(4).
(Kristianto J, Johnson MG, Afzal R, Blank RD.) Endocrinol Metab Clin North Am. 2017 03;46(1):51-62.
(Kristianto J, Johnson MG, Afzal R, Blank RD.) Transl Res. 2016 Nov 11.
(Meyer LA, Johnson MG, Cullen DM, Vivanco JF, Blank RD, Ploeg HL, Smith EL.) Bone. 2016 Apr;85:115-22.
(Kristianto J, Litscher SJ, Johnson MG, Patel F, Patel M, Fisher J, Zastrow RK, Radcliff AB, Blank RD.) PLoS One. 2016;11(2):e0148571.
(Yachoui R, Kristianto J, Sitwala K, Blank RD.) J Clin Endocrinol Metab. 2015 Nov;100(11):3971-4.
(Blank RD.) J Clin Densitom. 2015 Oct-Dec;18(4):455-6.