Title: EphB Kinases in Osteoblastic Stem Cell Niches Regulate Bone GrowthRajay A. Kamath, Brendan A. Daugherty, and M. Douglas Benson
Brendan Daugherty (Presenter)
Texas A&M University College of Dentistry
Rajay Kamath, Texas A&M University College of Dentistry
M. Douglas Benson, Texas A&M University College of Dentistry
Objectives: Substantial evidence shows that the membrane-bound ephrins and their Eph tyrosine kinase receptors regulate bone growth and homeostasis. Yet, little is known about which ligand/receptor pairs are involved or their mechanistic roles in bone biology. We previously described expression of the EphB2 and EphB3 kinases in calvarial sutures and of EphB3 in the proliferative zones of long bone metaphyses. As both of these sites are reported niches for osteoblastic stem cells, we hypothesized that ablation of these Ephs would result in dysregulated bone growth.
Methods: We examined knockout mice and wild type controls at ten weeks of age for phenotypes associated with loss of Ephs B1, B2, and B3 using plain X-ray and three-dimensional micro-CT analyses. EphB1 was included because it was observed in the periosteum, a known source of osteoblasts.
Results: X-rays of EphB1/2/3 triple knockout mice showed increased cortical thickness in long bones with fewer metaphyseal trabeculae compared to wild type controls, especially in the tibiae. Triple mutant calvariae appeared normally patterned, but had markedly increased radiolucency in the frontal bones, suggesting hypomineralization in that area. Micro-CT analysis of triple mutant femora confirmed their increased cortical bone volume compared to controls as well as increased cortical density and an increase in metaphyseal trabecular thickness. Despite the plain X-ray presentation of the frontal bones, triple mutant calvariae showed an overall increased bone volume/total volume (BV/TV) ratio compared to control calvariae.
Conclusions: These data indicate that Ephs B1, B2, and/or B3 tyrosine kinases regulate bone growth. Ongoing studies will identify the contribution of each individual EphB to bone development and healing.
Funding: NIH/NIDCR R01DE022804, The Baylor Oral Health Foundation, and the Texas A&M University Baylor College of Dentistry Office of Research and Graduate Studies