Robert Tracy Ballock, M.D.

Section Head, Pediatric Orthopaedic Surgery

I made a conscious decision to become an academic orthopaedic surgeon while a fourth year medical student at Harvard in order to satisfy my urge to understand mechanisms of musculoskeletal disease at the most fundamental level.I chose internship and residency training in orthopaedic surgery at the University of California, San Diego, primarily because of the strength of their orthopaedic research program and the reputation of the Department Chair, Dr. Wayne Akeson, as one of the pre-eminent orthopaedic surgeon-scientists in the country.

Following residency, I made an unusual career move for an orthopaedic surgeon by electing to spend two years in the intramural program at the National Institutes of Health in the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), learning fundamental techniques of cellular and molecular biology.Two months into my NIAMS experience, the director and only principal investigator in my lab left for the Mayo Clinic. Naively undeterred, I went knocking on doors until I had the good fortune of being taken in by Drs. Michael Sporn and Anita Roberts in the Laboratory of Chemoprevention at the National Cancer Institute. Their laboratory had recently discovered TGF-beta and they were interested in exploring the role of this new peptide growth factor in regulating growth and differentiation in the skeleton.During these two years, I focused on the role of TGF-beta in the growth plate and developed the three-dimensional pellet culture model of growth plate chondrocyte differentiation that is now used by many laboratories throughout the world.This experience resulted in thee publications, including first author papers in Developmental Biology and Journal of Cell Physiology.

While at the NIH, I forged an important collaboration with Dr. A. Hari Reddi in the National Institute of Dental Research who was working on the role of bone morphogenetic proteins (BMPs) in skeletal morphogenesis. Following my two years at the NCI, I spent a third year in his laboratory at Johns Hopkins where I formulated the serum-free, chemically defined culture conditions for growth plate chondrocyte pellet cultures that are also now used by many laboratories world-wide.For example, Dr. Brian Johnstone and colleagues at CWRU used our pellet culture model and serum-free, chemically-defined conditions to demonstrate for the first time that mesenchymal stem cells could undergo chondrogenesis in vitro. This year at Johns Hopkins was marked by several other key observations, including the discovery that terminal differentiation of growth plate chondrocytes was a default pathway that could be accelerated by thyroid hormone, and that morphogenesis of columnar cartilage in the growth plate could be recapitulated in our serum-free three-dimensional pellet cultures by addition of thyroid hormone.This work resulted in a first author publication in the Journal of Cell Biology.

Following these three years of basic science research training, I completed a clinical fellowship in pediatric orthopaedic surgery at the Texas Scottish Rite Hospital for Children in Dallas, and subsequently accepted a faculty position at the Rainbow Babies and Childrens Hospital and the Department of Orthopaedic Surgery at Case Western Reserve University and University Hospitals of Cleveland in 1994.

While at Rainbow, my research program began its focus on the molecular mechanisms of thyroid hormone action in the growth plate that continues to be the major thrust of our laboratory work today.We initially determined that the principal site of thyroid hormone action during skeletal maturation was regulation of the critical transition between cell proliferation and terminal hypertrophic differentiation in the growth plate.In addition to characterizing the expression of thyroid hormone receptors in this tissue, we also explored the interactions between thyroid hormone, vitamin D, and retinoic acid in regulating terminal differentiation of growth plate chondrocytes.Other work established an important link between thyroid hormone-induced terminal differentiation and upregulation of cell cycle proteins p21cip-1, waf-1 and p57 kip-1, indicating that growth arrest at the G1-S restriction point of the cell cycle is an obligatory step in the terminal differentiation process of growth plate chondrocytes.

In order to bring our growth plate studies into a more translational realm, while at Rainbow we also began to investigate the role of obesity in the dysfunction of the growth plate that results in slipped capital femoral epiphysis, a potentially devastating hip condition in adolescents. These studies have demonstrated that peroxisome proliferator activated receptors (PPARs), which are upregulated in response to a high fat diet, are also expressed in growth plate chondrocytes and interfere with the normal transcriptional activation function of thyroid hormone receptors in these cells, eventually resulting in the inhibition of terminal differentiation and matrix mineralization that allows the subsequent mechanical failure of the growth plate to occur.

In October of 2002, I left Rainbow to become Head of the Section of Pediatric Orthopaedic Surgery at the Cleveland Clinic, where we initiated DNA microarray studies of growth plate chondrocytes in order to identify the direct downstream genetic targets of the thyroid hormone receptor in the growth plate.These studies resulted in the surprising identification of the gene encoding carboxypeptidase Z (CPZ) as a direct target of thyroid hormone action.CPZ is an enzyme that removes C-terminal amino acid residues, particularly arginines, from proteins, and has also been shown to modulate Wnt signaling.Further experiments in our laboratory have demonstrated that Wnt-4, which is the principal Wnt family member expressed in the mammalian growth plate, contains a C-terminal arginine, and that removal of this C-terminal arginine enhances the biological activity of Wnt-4 in inducing terminal differentiation of these cells.

We have been fortunate to attract extramural funding to support these research efforts.This funding includes a Basil O’Connor Starter Award from the March of Dimes Birth Defects Foundation, a Career Development Award from the Orthopaedic Research and Education Foundation, and both a FIRST award (R29) and R01 award from the NIH.  In addition, we have received a score of 160 (6th percentile) on our most recent R01 submission and anticipate funding of this award in April 2007. These NIH grants place me in the elite group of a very small handful of orthopaedic surgeons in the country who have been awarded a single NIH grant.

--Robert Tracy Ballock, MD

• National Institutes of Health, 1990-1993

Orthopaedic Surgery

• North American Traveling Fellowship, American Orthopaedic Association, 1991
• Newton C. McCollough Award for Best Basic Science Paper, Pediatric Orthopaedic Society of North America, 1999
• Kappa Delta Award for Excellence in Orthopaedic Research, American Academy of Orthopaedic Surgeons, 2000
• The Harry J. Reich Lecturer, New York University-Hospital for Joint Diseases Department of Orthopaedic Surgery, 2003
• Cleveland's Top Doctors, 2007

• American Academy of Orthopaedic Surgeons
• American Orthopaedic Association (elected)
• Pediatric Orthopaedic Society of North America
• Orthopaedic Research Society
• American Society for Bone and Mineral Research

• OrthoPediatrics, LLC

• OrthoPediatrics, LLC