Site-Specific Load-Induced Expansion of Sca-1⁺Prrx1⁺ and Sca-1⁻Prrx1⁺ Cells in Adult Mouse Long Bone Is Attenuated With Age

Aging is associated with significant bone loss and increased fracture risk, which has been attributed to a diminished response to anabolic mechanical loading. In adults, skeletal progenitors proliferate and differentiate into bone-forming osteoblasts in response to increasing mechanical stimuli, though the effects of aging on this response are not well-understood. Here we show that both adult and aged mice exhibit load-induced periosteal bone formation, though the response is significantly attenuated with age. We also show that the acute response of adult bone to loading involves expansion of Sca-1⁺Prrx1⁺ and Sca-1⁻Prrx1⁺ cells in the periosteum. On the endosteal surface, loading enhances proliferation of both these cell populations, though the response is delayed by 2 days relative to the periosteal surface. In contrast to the periosteum and endosteum, the marrow does not exhibit increased proliferation of Sca-1⁺Prrx1⁺ cells, but only of Sca-1⁻Prrx1⁺ cells, underscoring fundamental differences in how the stem cell niche in distinct bone envelopes respond to mechanical stimuli. Notably, the proliferative response to loading is absent in aged bone even though there are similar baseline numbers of Prrx1 + cells in the periosteum and endosteum, suggesting that the proliferative capacity of progenitors is attenuated with age, and proliferation of the Sca-1⁺Prrx1⁺ population is critical for load-induced periosteal bone formation. These findings provide a basis for the development of novel therapeutics targeting these cell populations to enhance osteogenesis for overcoming age-related bone loss.