- ADJUNCT PROFESSOR Orthopaedics
ResearchSpecific Clinical/Research Interest: Systems approach to understand the interplay between genetic background and adaptative forces that define organ-level function and dysfunction.
Current Students: Siddharth Bhola, Mario Pinto
Research Personnel: Philip Nasser, Valerie Williams, Damien Laudier
Summary of Research Studies:
The management of a chronic condition like osteoporosis could be improved and tailored to the individual by identifying diagnostic tools that simultaneously reveal the underlying biology and that are related to biomechanical strength. One objective of this program is reduce fracture risk by identifying individuals earlier in life, before excessive bone loss has occurred and before the skeleton has become excessively fragile. The overall goal of this program is to decrease fracture risk later in life by building a healthy skeleton during childhood and by maintaining a healthy skeleton through the remainder of life. These two aspects represent the two 'arms' of this research program described in detail below.
How to Build a Robust Skeleton. These studies will identify the genetic and environmental factors that promote or interfere with the development of a robust skeleton. A robust skeleton is defined here as one that is well adapted to meet mechanical demands associated with weight bearing. Currently, these studies are focused on identifying the biological (genetic) factors that regulate variability in adult bone size, shape, and quality. These studies are conducted using inbred mouse strains, which provide a valuable model to study normal, non-pathologic variability in bone growth and development. A systematic, hierarchical approach has been developed and employed to close the gap between biology and bone fragility. With this systematic approach, each level of analysis involves identifying a trait (or several traits) that reveals the underlying biological control mechanisms.
These studies relate variability in adult whole bone mechanical properties, including measures of fragility, to the underlying physical bone traits (bone size, shape, composition), to the patterns of bone growth that define these physical bone traits, to the communication among and between osteoblastic and osteoclastic cell populations that regulate the patterns of bone growth. Continued work will ultimately determine how allelic variation gives rise to these phenotypes. This approach is applied to the mouse femur and the lumbar vertebral body. The latter research effort utilizes network algorithms (i.e., percolation theory) in order to relate global structural patterns defining load transfer mechanisms to the underlying biological processes that give rise to these structures. These studies will examine bones from inbred mouse strains, Recombinant Inbred strains, and Chromosome Substitution Strains. The genetic analyses are conducted in conjunction with Joseph Nadeau, PhD (Center for Computational Genomics; Case Western Reserve University). Matrix composition is being conducted in collaboration with Adele Boskey, PhD (Hospital for Special Surgery, New York, NY). Future studies will identify environmental factors (mechanical loading, nutrition) that promote or interfere with the development of a robust skeleton, and to test whether the biological response to these environmental factors varies with genetic background.
The outcome of studies in the mouse skeleton have lead to new hypotheses that are currently being tested in the growing human skeleton. One goal is to provide a useful feedback tool that allows the clinician to know whether the bones of a child are growing in a mechanically efficient manner. Current research shows that the human skeleton relies on a very similar network oftrait interactions as the mouse skeleton. The network of trait interactions has revealed a novel biological control that is shared across the general population. Ongoing research is directed identifying the genes that regulate this process.
How to Maintain Skeletal Strength with Aging. The decline in bone strength with age is generally thought to be a consequence of too much resorption and too little formation. However, aging also involves bone gain and this has generally been observed for the diaphysis of long bones in the form of periosteal expansion. Biomechanical principles dictate that the strength of bone not only depends on the balance between loss and gain, but also on the location of loss and gain. The results of a preliminary clinical study indicated that fracture incidence depended on the amount of periosteal expansion and not on the amount of endosteal resorption. Caucasian females with a low lifetime risk of fracturing showed an expansion of the periosteal width with age. In contrast, Caucasian females that presented clinically with a fracture did not show this restructuring. These results suggested that Caucasian females that fracture do not undergo an adaptive response that would maintain bone strength with age. Based on this study, we hypothesize that fracture risk depends on the degree of restructuring (i.e., adaptation) that occurs with age. This hypothesis will be tested using an existing longitudinal database (The Framingham Study), in collaboration with investigators at the Hebrew Rehabilitation Center for the Aged (affiliated with Harvard Medical School) and the Boston University School of Public Health. One of the outcomes of this research will be to identify the biological basis underlying variability in the adaptive nature of bone. Current studies are focused on the long bone diaphysis, which is easily imaged using plain film radiography. Future studies will move these concepts into the metaphyseal region (containing both cortical and cancellous tissues) where fractures typically occur.
Yakar S, Canalis E, Sun H, Mejia W, Kawashima Y, Nasser P, Courtland H, Williams V, Bouxein M, Rosen R, Jepsen KJ. Serum IGF-1 determines skeletal strength by regulating sub-periosteal expansion and compensatory trait interactions. J Bone Miner Res;: in press.
Jepsen KJ, Hu B, Tommasini SM, Courtland H, Price C, Cordova M, Nadeau JH. Phenotypic integration of skeletal traits during growth buffers genetic variants affecting the slenderness of femora in inbred mouse strains. Mammalian Genome, Epub 2008;.
Tommasini SM, Hu B, Nadeau JH, Jepsen KJ. Phenotypic integration among trabecular and cortical bone traits establishes mechanical functionality of inbred mouse vertebrae. J Bone Miner Res, Epub 2008;.
Jepsen KJ, Price C, Silkman LJ, Nicholls FH, Nasser P, Hu B, Hadi N, Alapatt M, Stapleton SN, Kakar S, Einhorn TN, Gerstenfeld LC. Genetic variation in the patterns of skeletal stem cell differentiation and progression during endochondral bone formation affects the rate of fracture healing. J Bone Miner Res 2008; 23(8): 1204-1216.
Courtland H, Nasser P, Goldstone AB, Spevak L, Boskey AL, Jepsen KJ. FTIRI microspectroscopy and micromechanical testing reveal intra-species variation in mouse bone mineral composition and matrix maturity. Calcified Tissue International 2008; 83(5): 342-353.
Tommasini SM, Nasser P, Hu B, Jepsen KJ. Biological co-adaptation of morphological and compositional traits contributes to mechanical functionality and skeletal fragility. Bone Miner Res 2008; 23(2): 236-246.
Jepsen KJ, Hu B, Tommasini SM, Courtland H, Price C, Terranova CJ, Nadeau JH. Genetic randomization reveals functional relationships among morphologic and tissue-quality traits that contribute to bone strength and fragility. Mammalian Genome 2007; 18(6-7): 492-507.
Tommasini SM, Nasser P, Jepsen KJ. Sexual dimorphism affects tibial size and shape but not tissue-level mechanical properties. Bone 2007; 40: 498-505.
Price C, Herman BC, Lufkin T, Goldman HM, Jepsen KJ. Genetic variation in bone growth patterns defines adult mouse bone fragility. Journal of Bone and Mineral Research 2005; 20(11): 1983-1991.
Jepsen KJ, Akkus O, Majeska RJ, Nadeau JH. Hierarchical relationship between genetically determined bone traits and whole bone mechanical properties in inbred mice. Mammalian Genome 2003; 14(2): 97-104.
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