Discoidin Domain Receptor 1 impacts bone microarchitecture with aging in female mice.

Discoidin Domain Receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagen(s), including collagen type I. deletion in osteoblasts and chondrocytes has previously demonstrated the importance of this receptor in bone development. In this study, we examined the effect of DDR1 ablation on bone architecture and mechanics as a function of aging. Femurs were collected from female global knockout (KO) and wild-type (WT) mice at 2, 6, and 12 mo of age and analyzed by high-resolution micro-computed tomography (μCT), mechanical testing, and histology. Primary monocytes were collected for in vitro osteoclastogenesis assays. Our studies on younger (2 mo) mice revealed no significant differences between the two genotypes and the microarchitectural and mechanical features had a similar trend as those reported earlier for osteoblast or chondrocyte specific knockdown. At an advanced age (12 mo), significant differences were noted across the two genotypes. μCT analysis showed a decrease in medullary cavity area as well as increased trabeculation in cortical and trabecular bone in the KO vs. WT mice. In addition, KO mouse bones exhibited reduced mechanical properties (lower peak load, yield load, and energy to yield) at 12 mo. Histological analysis revealed reduced osteoclast count in KO femurs at 12 mo with no significant difference in osteocyte count between the genotypes. In vitro, osteoclastogenesis was impaired in KO bone marrow derived cells. These results suggest that DDR1 deficiency adversely impacts osteoclast differentiation and bone remodeling in an age-dependent manner.