Sundar Srinivasan, Ph.D.
Dept. of Orthopaedics & Sports Medicine
Orthopaedic Science Laboratories
"Modeling Bone Mechanotransduction as an Emergent 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 an 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. Our current agent based models examine signaling
induced in bone cell networks by mechanical stimuli. Our data indicate
that when networked cells are exposed to cyclic stimuli, their collective
signaling operates at extremely poor efficiencies. In contrast, exposing
networked cells to rest-inserted stimuli synchronizes, enhances and sustains
signaling within the network. As well, our models permit correlation
and prediction of adaptive events that occur weeks downstream with signaling
that is induced in bone cells by mechanical stimuli on the order of seconds.
In sum, our 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.