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

Abstract

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. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Old Mice Have Less Transcriptional Activation But Similar Periosteal Cell Proliferation Compared to Young-Adult Mice in Response to in vivo Mechanical Loading

“…We also identified targets that had diminished upregulation in old mice, which may inform therapeutic approaches to restore the aged loading response. Next, we built on previous work analyzing the aged proliferative response to mechanical loading. Specifically, we used a strain‐matched study design to facilitate young‐adult versus old comparisons in vivo and BrdU incorporation to assess proliferation.…”

Toll-like receptor 4 signaling in osteoblasts is required for load-induced bone formation in mice

“…More study is required to determine if these TLR4-expressing cells generated after loading are mature osteoblasts, osteoprogenitors, or non-osteoblastic cells present in periosteum. 31 To investigate sex-related differences in the response of bone to Tlr4 knockout, both male and female mice were included in our analysis. Loss of Tlr4 in both male and female mice resulted in similar overall reductions in the key outcome parameter following axial forelimb compression—periosteal BFR/BS.…”

Increased deformations are dispensable for cell mechanoresponse in engineered bone analogs mimicking aging bone marrow

“…Next, instantaneous force and displacement data was collected during 20% compression at a rate of 10.8 mm/s ( Fig.2c ). Compression data was then input into MATLAB, converted to engineering stress and engineering strain, and then fit using a 5 th order polynomial [f(x) = ax 5 + bx 4 + cx 3 + dx 2 + ex +f] representing the instantaneous material behavior. Stress-strain curves for the calibration and HA gels are provided in Supplementary Fig.S1 .…”

“…[1][2][3] During habitual loading, MSCs provide necessary osteoblast populations to facilitate bone modeling. [4] Aging [5][6][7] and chronic unloading under microgravity [8,9] decrease exercise-induced bone accrual. While aging and unloading phenotypes are associated with decreased proliferative and osteogenic differentiation capacity of MSCs, [10,11] findings from in vitro replicative senescence [12] and simulated microgravity models [13] show that exposing MSCs to mechanically active environments improve these outcomes.…”