Multiscale Anabolic Bone Responses to Fluid Flow and Post-irradiation Loading

Open Access
- Author:
- Govey, Peter Michael
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 04, 2015
- Committee Members:
- Henry Joseph Donahue, Dissertation Advisor/Co-Advisor
Justin Lee Brown, Committee Member
Gregory Stephen Lewis, Committee Member
Christopher Niyibizi, Committee Member
Christopher Alan Siedlecki, Committee Member - Keywords:
- bone
mechanical loading
fluid flow
bone adaptation
radiation
irradiation
stem cell
mechanotransduction
bone marrow - Abstract:
- The long-term goal of this work is to reduce the burden of skeletal fractures by learning how to appropriate and guide the body’s inherent capacity for adaptive bone formation. This tissue-level adaptation to mechanical load is the end product of bone cells responding to physical phenomena in their microscopic niche. Our objective was to elucidate if, and how, the initial stimulation of cells might ultimately bring about bone adaptation to strengthen bones at risk for fracture, specifically those damaged by radiation therapy. Our study followed that sequence: we first examined the response of osteocytic cells—those thought to orchestrate the adaptive response—to in vitro fluid flow simulating the physical stimulation present at the microscopic scale upon loading. We identified novel cell signaling using high-throughput analyses of the whole gene transcriptome and proteome, enriched by network mapping and functional association databases. These results implicated inflammatory cellular recruitment, most notably via up-regulation of stem cell homing chemokines Cxcl1 and Cxcl2. Therefore, we examined recruitment of cells to loaded bones as we progressed to the whole tissue scale of adaptation. First, in mice in vivo, we determined compression loading was best suited for examining both trabecular and cortical tibia bone adaptation since cantilever loading brought about trabecular bone loss. Importantly, compression loading attenuated bone loss, and even added additional new bone in mice modeling our at-risk population of irradiated bone marrow transplant recipients. Hence, we propose that cancer and transplant patients subject to similar therapies may also retain robust physiological capacity for load-induced bone adaptation to alleviate fracture risk. To unify these cell- and tissue-scale observations, we examined recruitment of transplanted donor cells. We found no up-regulation of donor cell proportions in marrow of loaded bones, but a non-significant trend toward increased donor cell presence in loaded bone itself. In sum, these findings lead us to propose that when irradiated bones are loaded, fluid flowed osteocytes signal for recruitment of marrow- or vasculature-derived osteoprogenitors, thereby increasing adaptive bone formation and fracture resistance.