Sundar Srinivasan, Ph.D.
Dept. of Orthopaedics & Sports Medicine
Orthopaedic Science Laboratories
"Exploring Bone Mechanotransduction as an Emergent Adaptive
Phenomenon"
ABSTRACT
The central focus of our laboratory is to understand how bone cells and
tissues perceive and respond to mechanical stimuli and lack
thereof. For instance, we seek to understand how exercise makes
bone bigger and stronger and why disuse accompanying bed rest or space
flight causes bone mass to be lost. While the response of bone to
altered mechanical states is rapid, it is also occurs in a highly
localized fashion (e.g., tennis player have bigger bones in playing vs
non-playing arms). Additionally, bone response to mechanical
stimuli is focal even within a given bone and appears to occur,
paradoxically, at sites of minimal strain magnitude. More
recently, we observed that simply inserting a 10-s unloaded
rest-interval between load cycles transforms impotent cyclic loading
regimens into stimuli capable of dramatically enhancing bone formation
in the adult and aged skeletons. While these results have
attractive potential for application, the paradoxical bone responses at
sites of minimal strain and counterintuitive osteogenic potency of
rest-inserted loading highlight the general lack of knowledge of how
the process of mechanotransduction functions within bone. We
proposed that exploring bone mechanotransduction as an emergent
adaptive phenomenon might offer unique explanatory insights into how
bone cells and tissues perceive and respond to a epigenetic factor
critical to bone's form and function. We have begun to explore
this proposal by developing agent-based models of bone
mechanotransduction, an approach suited for the analysis of general
classes of complex adaptive systems. Agent based models are
unique in that they permit examination of how local, agent (or cell)
level functions and interactions between functions gives rise to
emergent properties at the global or network levels. In our
agent-based models, individual mechanosensory osteocytic cells were
assigned physiologically relevant functional characteristics including
threshold behaviors in response to stimuli and abilities to communicate
when constrained by finite metabolic resources. In this context,
we examined the responses of osteocyte cell networks to cyclic and
rest-inserted mechanical stimuli. Our data indicate that when
networked cells are exposed to cyclic stimuli, their collective
signaling power operates at extremely poor efficiencies. In
contrast, exposing networked cells to rest-inserted stimuli lowers
their thresholds for signaling by permitting recovery of metabolic
resources. In effect, rest-inserted stimuli result in
synchronization of cell activities and optimal network signaling
efficiency. In sum, our preliminary agent based models provide
unique insights into mechanisms underlying the counterintuitive
osteogenic potency of regimens such as rest-inserted loading and hold
promise in the broader exploration of how mechanotransduction functions
within bone.