Mice with a Disruption of the Thrombospondin 3 Gene Differ in Geometric and Biomechanical Properties of Bone and Have Accelerated Development of the Femoral Head

Abstract

Thrombospondin 3 (TSP3) is structurally similar to cartilage oligomeric matrix protein (COMP/TSP5), but its function is unknown. To determine the functional significance of TSP3, we generated mice with a targeted disruption of Thbs3. TSP3-null mice are viable and fertile and show normal prenatal skeletal patterning, based on Alcian blue/Alizarin red S staining. However, subtle and transient abnormalities were detected in the developing postnatal skeleton. Young adult TSP3-null mice are heavier than controls, and analyses of the geometric and biomechanical properties of long bones show increases in the moments of inertia, endocortical and periostal radii, and failure load. The bones of 9-week-old TSP3-null male mice also have a significantly greater cortical area. Most of these differences were no longer detected in 15-week-old mice. Microcomputed tomography scans showed that the trabecular bone proximal to the femoral head growth plate developed at an earlier time in TSP3-null mice than in wild-type mice. Thus, vascular invasion and ossification start in the femoral heads of TSP3-null mice at 9 weeks, whereas the wild-type femoral head is still composed of hypertrophic chondroctyes in a calcified matrix at 15 weeks. These results provide evidence for a role for TSP3 in the regulation of skeletal maturation in mice.

ACKNOWLEDGMENTS

This study was supported by grants HL 18645 and AR45418 from the National Institutes of Health to P.B., grant AR8562 to K.D.H., the University of Michigan Bone Center (AR46024), and a Postdoctoral Fellowship from the Arthritis Foundation awarded to S.H.

We thank Carol Ware and the Nathan Shock Center for Aging for assistance with blastocyst injections and generation of chimeric mice, Bernard Buetow for expertise in mouse histopathology, Janet Hall for expertise in statistical analysis, and Jennifer Tullis, Emily Stainbrook, Ken Kozloff, Suzanne Volkman, David Fischer, Rochelle Taylor, John Baker, and Daniel Meram for skillful technical assistance.