The Rolanette & Berdon Lawrence

2015 Highlights

Bone Disease ProgramO F T E X A S

Baylor College of Medicine®

Baylor College of Medicine®

The Rolanette and Berdon Lawrence Bone Disease Program of Texas is a collaborative research and clinical program of Baylor College of Medicine, MD Anderson Cancer Center and the University of Texas Health Science Center at Houston (UTHealth).

The Bone Disease Program seeks to improve the prevention and treatment of all degen-erative bone diseases, including osteoporosis, osteomalacia, Paget’s disease, and cancer metastasis to bone, by translating basic science findings into more effective treatment and prevention options.

Program Advisory Committee Members

Baylor College of Medicine: Lawrence C.B.Chan, DSc, MBBS; Thomas Hunt III, MDMD Anderson Cancer Center: Valerae O. Lewis, MD; Steven I. Sherman, MDUTHealth: Pending AppointmentExternal Advisor: Regis O’Keefe, MD, Washington University, St. Louis, MO

Robert F. Gagel, MD

Director, Rolanette and Berdon Lawrence Bone Disease Program of TexasProfessor and Head, Section of Bone and Mineral DisordersDepartment of Endocrine Neoplasia and Hormonal DisordersThe University of Texas MD Anderson Cancer CenterPresident, National Osteoporosis Foundation

Jacqueline T. Hecht, PhD

Co-Director, Rolanette and Berdon Lawrence Bone Disease Program of TexasLeah L. Lewis Distinguished ChairProfessor and Division Head, Pediatric Research CenterVice Chair for Research, Department of Pediatrics, UTHealth Medical SchoolAssociate Dean for Research, UTHealth School of Dentistry

Brendan H. Lee, MD, PhD

Co-Director, Rolanette and Berdon Lawrence Bone Disease Program of TexasRobert and Janice McNair Endowed Chair in Molecular and Human GeneticsProfessor and Chairman, Department of Molecular and Human GeneticsBaylor College of Medicine

The Lawrence Bone Disease Program of Texas (BDPT) is delighted to welcome its newest partner, The University of Texas Health Science Center at Houston (UTHealth).

“UTHealth’s partnership in the Program is a significant milestone,” emphasizes Dr. Robert Gagel, BDPT Director. “The BDPT has members from a number of UTHealth schools, including Medicine, Dentistry, Biomedical Sciences and Biomedical Informatics. These accomplished investigators and clinicians have in-depth expertise that complements and adds another dimension to the Lawrence Bone Disease Program of Texas, as evidenced by robust crosstalk and collaborations taking place between BDPT members.”

Jacqueline Hecht, PhD, is leading UTHealth’s participation in the Lawrence BDPT and has assumed the role of Co-Director. Dr. Hecht received a Master’s degree in Genetic Counseling from the University of Colorado Health Sciences Center and a PhD in Epidemiology from the UTHealth School of Public Health. She and her team of researchers bring a wealth of knowledge and expertise to the program due to their long-term experience in identifying genetic and molecular mechanisms that contribute to bone growth disorders and craniofacial malformations.

“There are more than 400 types of skeletal dysplasias, commonly referred to as dwarfism. We clinically follow a large number of patients with different short stature

Get to Know Our Newest Partner!

Dr. Jacqueline Hecht with Alex Berger, DDS student, at the 2015 Lawrence BDPT Scientific Retreat.

3

disorders, especially achondroplasia, the most common form of dwarfism,” explains Dr. Hecht. The research in her lab focuses on pseudo-achondroplasia (PSACH), a severe short stature disorder that is distinct from achondroplasia. PSACH becomes obvious between the first and second year of life when linear growth falls off. In 70% of cases, PSACH arises as a new mutation (or new event) in a family, and in 30% of cases it is inherited from a parent. Once the mutation occurs, an affected indi-vidual has a 50% chance with each pregnancy to pass the disorder to his or her offspring. PSACH is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. Mutant COMP is toxic to chondrocytes, the cells that control linear growth, causing them to die prematurely. The loss of chondrocytes results in dwarfism, limb deformities, joint pain and early onset osteoarthritis.”

In the 1990s Dr. Hecht and her team of researchers worked on mapping and identifying the gene that causes PSACH and characterized the molecular and cellular phenotypes that result from a range of COMP mutations. She states, “We developed a research program to study the cellular outcomes resulting from mutant COMP by generating a mouse model of PSACH. In 2013, Dr. Karen Posey, an Assistant Professor of Pediatrics at UTHealth and a co-investigator, reported that mutant COMP causes a severe inflammatory process in chondrocytes, a mechanism not previously recognized. Based on that mechanism,

anti-inflammatory and antioxidant therapeutic agents were tested and found to reduce the inflammation and allow for increased limb growth. These exciting and novel treatment approaches may someday be tested in PSACH.

For the past 25 years, Dr. Hecht’s group has also identified genetic variants that are respon-sible for nonsyndromic cleft lip and palate, a common birth defect that occurs in about 1 in 700 births and affects 4,000 newborns each year in the US. Patients with cleft lip and palate often have problems with speech, tooth abnormalities and facial scarring requiring a team approach to their management. The team consists of the geneticist, a plastic surgeon, a dentist, an orthodontist, a speech pathologist, a pediatrician, and an ENT physician.

Child with cleft lip and palate – before (left) and

after (right)Photos provided by

Dr. Sean Boutros.

A young patient with pseudoachondroplasia

4

that induces production of cilia during neural crest-derived mesenchymal cell differentiation in chondrocytes (cartilage-forming cells) and 2) that activation of these cilia is a critical factor for normal craniofacial development. Importantly, Dr. Komatsu brings knowledge and expertise to the Lawrence BDPT not previously available.

In addition to Dr. Hecht’s and Dr. Posey’s con-tributions, other faculty members at UTHealth are making a significant impact on bone and cartilage research. These individuals include Dr. Catherine Ambrose, an Associate Professor in the Department of Orthopedic Surgery, Dr. Naoki Nakayama, a Professor in Stem Cell Research, and Dr. Yoshihiro Komatsu, an Assistant Professor in Pediatric Research.

In 2014, Dr. Catherine Ambrose was the lead investigator on studies that defined the use of antibiotic-containing microspheres for the prevention of infection in highly contaminated orthopedic wounds. This technology holds great promise for treating difficult infections that occur after orthopedic implant procedures such as joint replacement. In addition, Dr. Ambrose is an expert in bone biomechanics and brings much needed expertise in biomechanical techniques and a core laboratory facility to the Lawrence BDPT.

Dr. Naoki Nakayama, the holder of the Jerold B. Katz Distinguished Professorship in Stem Cell Research at the UTHealth Medical School, studies the use of stem cells to repair human bone and cartilage defects. He has developed a well-characterized model in which pluripotent stem cells from a mouse embryo are isolated. Through the use of certain growth and differ-entiating factors, the pluripotent stem cells are directed to develop into adult cartilage cells and are used to fill skeletal defects in mice. Professor Nakayama is applying this same technology to the repair of cartilage and bone defects in humans.

Dr. Yoshihiro Komatsu concentrates on the role of primary cilia during craniofacial development. Cilia are small “hair-like” structures that sense movement and direct and signal the cell to activate growth and development processes. Dr. Komatsu’s work examines the mechanism by which growth factor signals stimulate the assembly of primary cilia and how these cilia receive a variety of environmental signals that regulate skeletal formation during embryonic development. He found 1) that bone morphoge-netic protein (BMP) is one of the signaling models

UTHealth Making an Impact

Above (left to right): Dr. Catherine Ambrose, Dr. Naoki Nakayama, Dr. Yoshihiro Komatsu

Below: Dr. Ambrose examines the strength of a plate used to stabilize proximal tibia fractures.

Phot

o by

Dre

w D

onov

an.

5

Teeth, and the supporting structures containing teeth (the mandible and maxilla), are specialized components of the skeleton. When teeth are lost and jawbones are worn away, an individual’s overall health and quality of life can be severely compromised. UTHealth’s School of Dentistry and the Center for Craniofacial

Research, are at the forefront of promising research and dental practices for a variety of conditions. This is accomplished by examining normal and abnormal craniofacial development and through tissue engineering and biomaterials,

and the microbiome (bacteria in the gastroin-testinal tract that regulates human physiologic

function). The Lawrence BDPT is very pleased that this important aspect of bone health is being addressed.

Dental agenesis, or the congenital absence of one or more permanent teeth, is the most common dental congenital abnormality in humans, however, its cause(s) is unknown. Drs. Ariadne Letra and Renato Silva’s research focuses on identifying the causes of tooth agenesis and other developmental tooth and palate defects by combining genetic and biologic approaches. Using next-generation DNA sequencing, they identified and are studying novel gene variants causing tooth agenesis in humans. In addition, they are using zebrafish to further understand the role of specific genes in tooth development and disorders affecting it. It is their hope that this basic information can be used to improve genetic counseling for these disorders and eventually be used in therapeutic treatment strategies.

Dr. Junichi Iwata, Assistant Professor, focuses on understanding the molecular and cellular mechanisms that cause craniofacial birth defects. In particular, he is interested in the WNT family of signaling molecules that are an essential component for normal bone develop-ment and also regulate developmental and regenerative processes in skeletal muscle. Dr. Iwata’s research highlights the role that WNT and its down-stream signaling partner, beta-catenin, have on normal skeletal muscular development. He and his team have generated mouse models that make it possible to study the WNT/beta-catenin signaling pathways and define how these pathways cause skeletal birth defects.

Importance of the UT Dental School to the Lawrence BDPT

Dr. Ariadne Letra

Dr. Renato Silva

Dr. Junichi Iwata6

People are living longer than ever before, yet an estimated 2 million Americans suffer an osteoporotic fracture each year at an estimated annual cost of $19 billion to the Medicare system. Adding to the problem, over 80% of patients who experience an osteoporotic fracture do not receive bone health evaluation and remain at an exceedingly high risk of a future fracture.

successfully developed the “Own the Bone” Program at Northwestern University and participated with other institutions nationally. “I am very enthusiastic about improving med-ical care for patients who have experienced an osteoporotic fracture,” says Dr. Edwards. “Our primary goal is to prevent a second fracture! In keeping with this goal, we also plan to develop health information algorithms to better identify and treat fragility fractures as well as a data-base of fragility fractures that can contribute to future research.”

In early 2015 Drs. Gagel and Edwards met with key hospital physicians, researchers, and administrators to explain the advantages of this proposed initiative in greater detail. Subsequently, they outlined the benefits of this service to Texas Medical Center (TMC) CEOs, and each CEO is appointing a hospital repre-sentative to participate on a Fracture Liaison Service Committee. What makes this program

Dr. Robert Gagel, Director of the Lawrence BDPT and President of the National Osteoporosis Foundation, and Dr. Beatrice Edwards, an Associate Professor specializing in Geriatric Medicine at MD Anderson, have been at the forefront of efforts to change this large gap in medical care.

Through the Lawrence BDPT, they want to make a difference in this care standard – starting with a Fracture Liaison Service that can be offered right here in Houston at individual hospitals within the Texas Medical Center. Such services have shown demonstrable success as evidenced by the prevention of recurring fractures, less physical disability, and fewer nursing home placements. “Having a number of major hospitals in a defined geographic location definitely lends itself to developing a centralized and efficient program,” states Dr. Gagel. “We estimate that there may be more than 5,000 hip and vertebral fractures annually within the TMC patient population, of which only 1,000 are receiving evaluation for osteoporosis treatment.”

The central Fracture Liaison Service will be directed by Dr. Edwards with assistance from a nurse practitioner and a physician champion at each participating institution. Dr. Edwards

X-Rays of Osteoporotic Fractures

Taking Care of PatientsLiving Longer; Living Fracture-Free

Dr. Beatrice Edwards

7

truly unique is that it is a cross-medical center effort involving multiple hospitals within the TMC. Although the most significant reason for hospitals to participate is improved healthcare for patients who suffer osteoporotic fractures, hospitals that participate in this service are expected to benefit in other ways.

In 2013, the Centers for Medicare and Medicaid and the Joint Commission developed measures to assess the quality of medical care after a fracture, and these measures will impact the amount of reimbursement hospitals in the

United States receive. The Joint Commission may include a similar metric among its criteria for certification, and the most used healthcare measurement tool in the nation (HEDIS) may follow suit. “I am confident this service will help hospitals in the Texas Medical Center meet quality standards and be rewarded for doing so,” states Dr. Gagel. “The extra incentive is a plus, but what is most important is saving patients from future fractures and the probability of a shortened life span. We want people to live long and well in their senior years.”

Memorial Hermann Hospital in the Texas Medical Center is the primary, private teaching hospital for UTHealth. On May 4, 2015, Memorial Hermann Hospital opened a Fragility Fracture Service that provides rapid Emergency Room stabilization of patient fractures and coordinates the delivery of care from the time of entry until the time of dis-charge. What makes this Service particularly exceptional is the care continuity it provides

How does a Fracture Liaison Service Work?

to patients who may be at risk for another fracture. Prior to discharge from Memorial Hermann Hospital, the patient is referred to the newly formed Bone Health Clinic, located in the Department of Orthopedic Surgery at UTHealth. In addition to providing outpatient care for Memorial Hermann fracture patients, the Bone Health Clinic provides assessment and treatment for any individual at risk for osteoporosis and fragility fractures. The Clinic works in collaboration with UTHeath Geriatric Osteoporosis Clinic to ensure that there is a full continuum of preventive man-agement and bone health care. The Fragility Fracture Service is an excellent model for how other hospitals in the TMC can address fracture prevention.

8

Baylor College of MedicineLeading Brittle Bone Disorders Consortium of the Rare Disease Clinical Research Network

Baylor College of Medicine was selected by the National Institutes of Health to lead the Brittle Bone Disorders Consortium of the Rare Disease Clinical Research Network, a new, multi-center initiative that will focus on understanding and providing better therapeutic options for rare diseases characterized by bone fragility and fractures. The consortium includes nine other leading centers in the United States and Canada.

The consortium is supported by several national organizations including the National Institute of Arthritis, Musculoskeletal, and Skin; the National Institute of Child Health & Human Development; and the Office of Rare Diseases in the National Center for Advancing Translational Sciences.

The Consortium will seek to gain a better understanding of all genetic forms of the disorder.

In recent research that Dr. Brendan Lee, Lawrence BDPT Co-Director published in the journal, Nature Medicine, Dr. Lee proposed a new approach for the treatment of brittle bone disease. The consortium will initiate a phase I clinical trial of an anti-TGFβ antibody in patients with severe osteogenesis imperfecta. The consortium will also initiate pilot studies focused on developing quality of care measures and identifying new biomarkers. The consortium will team up with the Osteogenesis Imperfecta Foundation to train a broad spectrum of health-care providers in the diagnosis and treatment of brittle bone disease and clinical researchers in osteogenesis imperfecta.

Institutions Participating in the Brittle Bones Disorder Consortium

KennedyKrieger Institute

University ofSouth Florida

Marquette University and Shriners Hospital, Chicago

Hospital forSpecial Surgery

Shriners Hospitalfor Children

UCLA

Oregon Health SciencesUniversity

University ofWashington

Childrens NationalMedical Center

Baylor College of Medicine

9

MD Anderson’s Bone Health Clinic continues to be an important resource for cancer patients who have various bone health concerns. In some cases, patients may be predisposed to bone loss as they age or because they don’t understand the importance of preventative measures, such as taking calcium and vitamin D. In other cases, the cancer therapies that are essential to a patient’s recovery can lead to a loss of bone mass. MD Anderson patients who have questions about their bone health can easily be referred to the Bone Health Clinic by their physicians.

The Clinic has twelve consulting physicians. Dr. Mimi Hu is the current rotating Director of the Clinic, and Dr. Huifang (Linda) Lu is Co-Director. The Clinic’s core group of physicians also collaborates with other

MD Anderson specialists to ensure all aspects of patient care are provided, as needed. Those who are central to this multidisciplinary approach include oncologists, radiologists, pain control specialists, nutritionists and orthopedic surgeons.

Patients who are seen in the Clinic are eval-uated in various ways including bone density scans, blood testing to check for vitamin D deficiency and indications of abnormal calcium deficiency, urine testing to check for calcium loss, radiography to check for fractures, and other testing for causes of bone loss. If medical therapy is indicated, the health care provider will discuss options and work with the patient in selecting a plan that is tailored to his or her specific needs.

Dr. Mimi Hu explaining bone loss to a patient.

MD Anderson’sBone Health Clinic

Dr. Huifang (Linda) Lu consulting with patient in clinic.

10

Dr. Sandesh Nagamani, an internist and clinical geneticist leads Baylor College of Medicine’s Clinic for Metabolic and Genetic Disorders of Bone (CMGB). This clinic treats adult patients with a variety of bone disorders such as osteoporosis and osteomalacia, metabolic bone diseases due to abnormalities in calcium and phosphorous metabolism, and genetic disorders of bone that include osteogenesis imperfecta (commonly known as “brittle bone”), heritable defects of collagen, and developmental abnor-malities of bone.

Dr. Nagamani tests new treatments in adults with these genetic disorders and develops new diagnostic tests to identify strong genetic determinants of bone disease. The Clinic is particularly designed for patients with a family history of bone disease and Tanya Eble, a certified genetic counselor, assists in this process. Services also include pain manage- ment, physical therapy and rehabilitation, orthopedics, genetic testing services, and an infusion center.

BCM Addressing a Wide Range of Skeletal Problems

11

“Precise” is a word that aptly describes the surgical skills used by Dr. Thomas Hunt III, Professor and Chair of Orthopedic Medicine at Baylor College of Medicine. As a specialist in the hand, wrist, and elbow, Dr. Hunt meticu-lously navigates a complex maze of bones and joints, ligaments and tendons, muscles, nerves, and blood vessels to perform the procedures by which he treats a multitude of problems. The relationship between the lower arm, wrist, and hand is a delicate and interconnected one, and he is no stranger to difficult cases.

“By nature, I’m a perfectionist,” states Dr. Hunt. “That’s why I chose this area of medicine.” He continues: “Hand surgery is very exacting, and I feel a tremendous sense of accomplishment in giving people back sensation and/or movement they lost due to trauma or age, or relieving them of debilitating pain. Additionally, the technical aspects of performing detailed hand surgeries are very interesting to me.”

A Close-up Look at Dr. Thomas Hunt’s Handiwork

After receiving his medical degree from Vanderbilt School of Medicine, Dr. Hunt returned to his home state of Kansas. There he completed his residency and graduate training in Orthopedic Surgery at the University of Kansas followed by specialized training in hand surgery.

“I believe that all of our experiences provide us with insights and contribute to who we are and how we want to practice medicine,” states Dr. Hunt. “My first position after training was with Virginia Mason Medical Center in Seattle. This institution is known for its emphasis on patient safety, an absence of errors, and efficiency, all of which are adapted from the Kaizen philosophy of continuous improvement. I took away a number of positive aspects from that experience.

In 2013 Dr. Hunt came to Baylor College of Medicine as Professor and Chair of Orthopedics, and he is particularly delighted to be at the forefront of advancements in orthopedic research. “I perform a significant number of

12

Texans and treats many other professional league players who are referred by team physicians. His greatest challenge relates to the functional expectations of the patients. Dr. Hunt explains: “The NFL athletes I treat represent some of the most difficult cases I’ve handled. Hand function is very critical to these athletes and can make the difference between having a career, or none at all. The same is true for the pro golfers that I treat.

The one piece of advice that Dr. Hunt imparts to all of his patients is to keep moving. “Whether it’s walking, working out in a gym, or playing ball, engaging in some kind of physical activity every day is important. Speaking for myself, I have four kids, ages eight through thirteen, so inactivity is not even an option.”

arthritis-related surgeries,” states Dr. Hunt, “and Baylor’s Bone Center is very involved with research on degenerating cartilage and bone, commonly referred to as osteoarthritis. Osteopenic fractures are common in this population, and one of our important goals is to translate the Center’s research into improved procedures and treatments for osteoarthritis.”

Dr. Hunt is also focused on understanding the cause of torn ligaments in the wrist. “First, I’d like to understand why some people are more likely to tear their ligaments than others. Next, I’d like to find better methods of repairing such tears. Currently we transfer tendons; however, I’m not convinced this is the best solution.” Again, Dr. Hunt emphasizes the important role research will play in finding answers to these questions. He states, “If we can understand the essential difference between those patients that tear ligaments, or tear them more frequently than others, we then have a mechanism to determine the genetic basis of those differences, identify who is more likely to sustain injuries, and develop specific treatment programs for these individuals.”

Dr. Hunt likens this approach to the way brittle bone disease was handled. He notes that it is important to isolate the problem in a subset of people to determine the genetic components they share before attempting to find an appropriate treatment. Dr. Hunt remarks, “As the Bone Center moves forward to tackle Ehlers-Danlos Syndrome and other ligamentous problems, I’m planning on being very involved in this work. Ehlers-Danlos Syndrome is a pathological state, and if we can understand it, we can apply that understanding to other problems. For example, we potentially could identify a protein that would be injected into the ligaments to make them stronger.”

In addition to Dr. Hunt’s Chair-related responsi-bilities, he is a team physician for the Houston

“Osteopenic fractures are common in this population, and one of our important goals is to translate the Center’s research into improved procedures and treatments for osteoarthritis.”

Dr. Hunt performing hand surgery.

13

The Quest for Answers Never EndsMD Anderson Bone and Cancer Working Group

Most MD Anderson cancer center researchers focus on a specific cancer type such as breast or prostate, or they work on an overarching question that applies to all cancers. Additionally, they are likely to work in proximity to other researchers who have overlapping interests. This type of environment is conducive to the exchange of ideas and collaboration.

MD Anderson Bone and Cancer Working Group

The scientific environment for those investi-gating bone in the context of cancer is a bit different. Although these investigators may share an interest in a particular cancer type with other colleagues, they may not be working alongside others who focus on cancer’s effects on bone.

Dr. Robert Gagel and the Lawrence Bone Disease Program of Texas (Lawrence BDPT) are working to ensure that promising bone researchers at MD Anderson have opportunities to discuss and collaborate with others who have similar or related interests. Currently, the working group has participants from Genetics, Myeloma, Leukemia, Genitourinary Medical Oncology Research, Orthopedic Oncology Research, Translational Molecular Pathology, and the Bone Histomorphometry Core.

On a monthly basis, talented investigators within MD Anderson meet to share their grant proposals and receive constructive feedback from the group. Additionally, the group is working together to prepare a hypothesis-driven, multidisciplinary, translational cancer research project that will be submitted to internal (MD Anderson) judges for review. MD Anderson provides seed funding to facilitate collaborative research among teams of investigators with the goal of obtaining a peer-reviewed multi-investigator grant award. Historically, a large percentage of the proposals that are submitted for external funding are successful at receiving P01, SPORE, or CPRIT multi-investigator grant awards.

14

The National Institute of Health selected six clinical research institutions across the United States to combine resources and advance medical knowledge for rare diseases. As the skeletal system is involved in over 40% of genetic conditions, the infrastructure and strength of the bone research community within the Bone Disease Program of Texas was integral in attracting this initiative. Baylor College of Medicine was one of the sites chosen and was awarded a $7.3 million dollar grant to support and expand its research in all organ areas and lend specialized expertise to other network members that may have difficulty in diagnosing rare diseases. As a core feature of the program, all of the institutions in the network will practice an interdisciplinary approach in evaluating patients.

The Lawrence BDPT Contributes to Advancing Medical Knowledge for Rare Diseases

Dongsu Park, PhD, an Assistant Professor in Molecular and Human Genetics at Baylor College of Medicine, is intent on learning more about the biology of mesenchymal stem cells in tissue regeneration and cancer – and for good reason. These cells are required to maintain and regenerate most tissues including muscle, brain, blood and bone. With regard to bone he explains, “If a person has a bone injury, the mesen-chymal stem cells receive signals that it’s time for them to proliferate and become bone forming cells at the site where new bone is needed. Although the mesenchymal stem cells do not make new bone per se, they have very strong cross-communications at the injured site. Without their presence, the bone simply cannot repair itself.”

Dr. Dongsu Park Intent on Learning More about Mesenchymal Stem Cells and Bone

15

properly. “This is a very important area we need to study,” says Dr. Park.

Dr. Park takes great pride in his lab’s imaging equipment and is quick to mention that it has one of the most advanced systems in the world. States Dr. Park, “We are able to engage in many collaborative projects with the imaging team at Massachusetts General Hospital and with bone teams in the Texas Medical Center, including the achilles tendon imaging project developed by Dr. Brendan Lee. Tendon regeneration and repair is a significant issue for many people who experience repeated injuries. Often it is difficult for these individuals to recover. We believe it is important to understand the many activities that occur during the repair and regenerative process.”

When asked which aspect of science is most rewarding to him, Dr. Park responded, “I receive tremendous pleasure in trying to answer some of the important questions in basic biology that will lead to improvements in the medical field. The small contributions of many scientists can ultimately lead to big shifts in caring for patients. Also, there is nothing I enjoy more than watching cells move. To me, that is very exciting!”

One of Dr. Park’s important goals is to under-stand how mesenchymal stem cells operate in live animals. He is particularly interested in the mechanisms that regulate their movement and growth and their interactions with hematopoietic stem cells (cells that primarily are found in bone marrow and mature into different blood types). Currently, he is working with mice to obtain more insight into the bone regenerative process. Using live-animal imaging technology, he can illustrate critical events in the early repair process with the use of fluorescent colors. Injury sites are sequentially imaged to show mesenchymal/skeletal stem cells relocating to the injury, increasing in number and differentiating into bone forming osteoblasts (cells that produce a matrix that becomes mineralized). With this technique, it is possible to assess the role that individual cells contribute to the healing process.

I also plan to use live-animal technology to investigate the clinical relevance of mesen-chymal stem cells in inherited bone disorders and malignant bone diseases. These include osteoporosis, osteosarcoma and cancer bone metastasis,” explains Dr. Park. He emphasizes that if cancer metastasizes to bone, the mesenchymal stem cells cannot do their work

*Resources from the Lawrence BDPT were used to purchase a state-of-the-art microscope that makes it possible to image and characterize unique cells involved in the healing process.

The Role of Skeletal Stem Cells (SCC) in Fracture Healing.*

Intra

vita

l im

agin

g of

bon

e in

jury

Mx1/Tom

ato/Ocn-GFP

Chase Mx1+SSCs in fracture healing

Dr. Dongsu Park

16

“Multiple myeloma is a malignancy in which the plasma cells (bone marrow cells that nor-mally make antibodies that protect us from infections) become cancerous,” explains Jing Yang, PhD, an Assistant Professor in the Department of Lymphoma/Myeloma at MD Anderson

Cancer Center. “These myeloma or plasma cells produce several substances that promote the growth of the malignancy and also cause destructive bone lesions. It is not uncommon for individuals with myeloma to have hundreds of bone lesions in which the myeloma stimulates the osteoclasts - the type of cell that normally initiates remodeling of bone - to cause large-scale destruction of bone that can be painful.” Dr. Yang adds, “I am focusing on how myeloma cells cause abnormalities in bone because I know the difficult problems that patients can face, and I want to be able to make a difference.”

Work over the past 20 years has shown that myeloma cells produce several factors including Rank Ligand (RANKL) and several interleukins. RANK ligand stimulates the formation of osteo-clasts and activates bone breakdown. Normally, this is a highly regulated event, but in myeloma, RANKL is produced continuously in excessive amounts leading to large-scale bone destruction.

“My current work is focused on another mechanism by which myeloma cells alter bone formation,” explains Dr. Yang. “I examined a myeloma cell protein, integrin alpha4beta1 (α4β1), which interacts with a receptor, VCAM-1, in bone marrow mesenchymal stem cells to alter normal development of these cells. Normally, these cells would develop from a stem cell and become an osteoblast or bone-forming cell.” Dr. Yang has discovered

that the expression of α4β1 leads to an altered differentiation pathway, creating fat cells instead of bone-forming cells. Indeed, if one looks at the marrow from a patient with myeloma, one sees a proliferation of fat cells. She is currently working to understand how this differentiation defect leads to myeloma bone disease, and more importantly, has developed strategies to reverse this process and help patients with myeloma-induced bone disease make new bone.

Although Dr. Yang’s work is focused specifically on cancer, these observations -- particularly the role of α4β1 integrin in the regulation of bone marrow differentiation-- have important implica-tions for bone health in normal individuals. For example, one side effect of the current obesity epidemic in the United States is an increase in the number of fat cells in the marrow and a consequent decrease of number of osteoblast or bone-forming cells. This not only causes diabetes mellitus and other deleterious effects of obesity, but can also lead to a reduction of bone mass. Dr. Yang is currently performing studies to determine whether α4β1 is respon-sible for the alterations seen in bone in the context of cancer.

Jing Yang, PhD ProbesHow Myeloma Cells Cause Bone Abnormalities

Bone lytic lesion caused by multiple myeloma.

Dr. Jing Yang

17

Every year the Lawrence BDPT hosts a lively Scientific Retreat at which three promising investigators are awarded $45,000 research seed grants to pursue their bone research. Awards also are made to three investigators who participate in a poster competition. Eligible research projects cover important aspects of bone biology, bone formation, bone metastases, and bone health in cancer patients. The following scientists/physician-scientist were the 2015 award winners:

Lawrence AwardsEnable Promising Investigators to Advance

Below (left to right): Berdon Lawrence Hosts 2013, 2014 Research Award Winners–Venkata Lokesh Battula, PhD; Xin Zhou, PhD; Berdon Lawrence; Huifang (Linda) Lu, MD, PhD; Jun Wang, PhD; Dongsu Park, PhD

Left: Kyu Sang Joeng, PhD, Baylor College of Medicine, “Identification of the Function of WNT1 in bone homeostasis.”

Center: Karen Posey, PhD, UTHealth, “Novel model of adult-onset OA induced by targeted dysfunction of articular chondrocytes.”

Right: Sanjay N. Mediwala, MD, Baylor College of Medicine, “Bone quality response to lifestyle intervention in older adults with diabetes.”

18

The Histomorphometry Laboratory at MD Anderson performs histomorphometric analyses of non-decalcified

bone specimens from genetically modified animals and long bones injected with cancer cells.

Core Facilities: The Program’s Research Work Horses

A robust research program requires state-of-the-art equipment and services that are generally too costly for individual investigators to purchase and maintain. The Lawrence BDPT is committed to the establishment and support of core facilities for its members, and we are pleased to report that the Program now has a total of six core laboratories. For Example:

The computerized tomography scanner at Baylor College of Medicine can create a three dimensional model of bone and capture bone detail at six microns.

Images from the MicroCT Core: Lack of the hormone calcitonin (left) causes profound remodeling of the

vertebral body resulting in increased numbers of trabeculae. This creates more and thinner trabeculae

than seen in the vertebral body from a normal mouse shown on the right. MicroCT provides a technique for

demonstrating these differences without having to destroy the bone. 19

When Dr. Jim Dennis, an Associate Professor in the Department of Orthopedic Surgery at Baylor College of Medicine, is asked what he likes best about being a scientist, his response is brief and exuberant: “There’s nothing more exciting than seeing something that no one else in the world has ever witnessed.” Recounting one such an experience, Dr. Dennis explained that he was using monoclonal antibodies with a particular muscle protein to determine the distance between carefully assembled sarcomeres (the basic unit of muscle) in the electron microscope. Sarcomeres are involved in muscle twitching, and the speed of twitching can affect spacing. No one had previously tried this with monoclonal antibodies, and he was anxious to know the outcome.

After several weeks of preparing materials and not seeing any results, he refined the antibodies to a point of high purity and concentration prior to using them on the muscle samples. As he turned up the electron beam to examine his experiment late one evening, he couldn’t believe what he saw – all of the spaces were perfectly aligned, and he was the first one to observe this unique spacial patterning. “It’s those moments of scientific discovery that keep scientists going,” remarked Dr. Dennis. The results were part of Dr. Dennis’s first publication in the Journal of Cell Biology.

Dr. Jim Dennis Investigates Skeletal Muscle

20

Dr. Dennis assumed a faculty position at Baylor College of Medicine in 2014 after serving in faculty appointments at Case Western Reserve University in Cleveland and the Benaroya Research Institute in Seattle. During his appointment at the Benaroya Research Institute, he focused on skeletal muscle research, osteo-porosis, cardiac repair, and tissue engineering.

One particular tissue engineering project concentrated on muscle replacement. “This type of work is very important to people with severe trauma, such as battlefield injuries or car accidents,” said Dr. Dennis. “Although muscle is able to repair itself, it cannot fill an empty gap, and there has to be a way to fill the empty space.” Dr. Dennis explained that his team developed a collagen scaffold that was connected to sutures and put under tension. Satellite cells, acting as muscle precursors, were then added to the scaffold. The satellite cells assembled into preliminary muscle fibers called myotubes, and the entire scaffold was implanted into rats.

Purifying satellite cells has been a problem in the past, and Dr. Dennis’s team was able to improve the purification process to obtain greater than 90% satellite cell purity. He continues to work on this research at Baylor College of Medicine and was invited to submit preliminary results to the Department of Defense in 2014. Dr. Dennis is quick to point out that research in one particular area often crosses over to another area. For example, he has a funded study to pursue tissue engineering for trachea reconstruction, and much of what was learned about chondrocytes, relative to trachea reconstruction, can be applied to total joint resurfacing.

A primary goal of joint replacement research is to develop a living replacement for joints instead of the plastic and metal parts that are currently being used. With people living longer, a large percentage of patients who have joint replacement surgery often need a second

revision. “The problem with that is that there may not be enough bone available for multiple joint revisions,” states Dr. Dennis. “If we could engineer a living replacement by taking cartilage from a person’s ear, nose, or knee – grow it in

culture, shape it to fit the knee, and get it to integrate into the knee – we could help millions of people have a better quality of life. There is still a significant amount of work to be done in this area, but progress is being made.”

Dr. Dennis and his colleagues are making advances in generating sheets of human cartilage and are better at expanding human chondrocytes. They also know how to add growth factors such as bone morphogenetic protein (BMP2) and thyroxine, as well as improve biomechanical strength. “If we can make cartilage stronger, there is the possibility that we could one day position a sheet of cartilage that would integrate into the bone and delay or prevent revision surgery.”

When Dr. Dennis is not in the lab, he likes to travel, sail, and watch football and soccer. With a bit of a smile, he says, “My secret obsession is to play Texas Hold-em Poker, but, ironically, I haven’t played very much since I moved to Texas. Guess I’ll need to fix that!”

Knee bone connected to the thigh boneThigh bone connected to the hip boneHip bone connected to the back bone…And muscle is connected to them all.

Dr. Dennis takes images of engineered cartilage and processes the images to analyze cell content in five distinct regions of the cartilage.

21

Opportunities to Learn and Share Knowledge

On an annual basis the Lawrence BDPT invites outstanding national and international scientists in the field of skeletal biology to present seminars to program members. Speakers assembled for the 2014-2015 series included many well-known bone experts including Dr. David Dempster, Professor of Clinical Pathology, Helen Hayes Hospital, New York, N.Y.; Dr. Marian Young, Chief, Molecular Biology of Bone and Teeth Section, National Institutes of Health/NIDCR; and John Bilezekian, Professor of Medicine and Pharmacology, Columbia University, New York, N.Y. Speakers arrive a day before their presentations so they can meet with both accom-plished and junior investigators in small groups and individual sessions.

Seminar Series

The Bone Research Club is a forum that high-lights exciting new research in skeletal biology and bone disease and provides a platform for scientific interaction among clinicians and researchers from the Program’s three institu-tions. The atmosphere at this evening event is energetic but relaxed, and all agree it’s a perfect way to end a busy day in the lab or clinic.

Bone Research Club

22

We wish to express our sincere gratitude to the many donors who have contributed to the Lawrence Bone Disease Program of Texas and,

in particular, Rolanette and Berdon Lawrence for their major contributions.

Robert F. Gagel, MDDirectorThe Rolanette and Berdon Lawrence Bone Disease Program of Texas

Jacqueline T. Hecht, PhDCo-DirectorThe Rolanette and Berdon Lawrence Bone Disease Program of Texas

Brendan H. Lee, MD, PhDCo-DirectorThe Rolanette and Berdon Lawrence Bone Disease Program of Texas

Baylor College of Medicine®

Skeleton Illustrations by Jordan Pietz MA and Dave Aten MA Visual Art: © 2015 The University of Texas MD Anderson Cancer Center

Baylor College of Medicine One Baylor Plaza, Room 814Houston, Texas 77030

MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 1461Houston, Texas 77030

UT Health 6431 Fannin Street, MSB 3.136 Houston, Texas 77030

www.BoneDiseaseProgram.org

For information contact:

Charlotte Cherry Administrator, Baylor College of Medicine CCherry@BCM.edu

Lea Tatar Administrator, MD Anderson Cancer Center LSTatar@MDAnderson.org