ORIGINAL PAPER Stress Response by Bone Cells and Implications on Microgravity Environment Rommel G. Bacabac • Jack J. W. A. Van Loon Published online: 12 February 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Osteocytes are commonly referred to as the professional mechanosensors in bone tissue. Despite recent advances in the study of how bone tissue adapts to mechanical loading, much remains not understood con- cerning the cellular mechanisms involved. We have shown that bone cell monolayers in vitro release signaling mole- cules in response to dynamic stress loading in a rate- dependent manner. Fluid shear stress induces high release of nitric oxide (NO) at high rates, whereas vibration stress promotes high NO release but low prostaglandin E2 (PGE2) release at high rates, indicating the specificity for signaling molecule of the type of stress. Also, we show evidence that bone cells require a stress threshold in order to respond to loading. These observations collectively provide basis for hypothesizing a model defining tissue- mimetic mechanosensitivity as a function of the rate of stress above a threshold. Finally, at the cellular level, we show that shape and stiffness, evidently due to underlying cytoskeletal structure, contribute to mechanosensing. This leads to the notion that the mechanical properties of cells are a prerequisite to their tissue-level emergent mechano- sensing behavior. Therefore, a condition of disturbed mechanics due to extreme unloading, as in an environment under microgravity, may lead to impaired mechanosensing. Keywords Osteocytes  Shear stress  Mechanosensing  Cell mechanics  Microrheology  Cell traction  Microgravity  Cytoskeleton  Biopolymers  Networks Introduction Bone cell tissue adapts its mass and structure in response to mechanical loading [1]. However, the cellular mecha- nisms involved remained poorly understood. This life-time adaptation to loading enables a transformation for more efficient support of the organism’s weight. As a biological function, the loading information is commonly accepted to be communicated to the effector cells that form new bone or resorb old bone [2, 3]. The flow of interstitial fluid in vivo is hypothesized to be the most likely stimulus arriving on the surfaces of osteocytes and bone lining cells [2–4]. Bone cells in culture respond to different types of mechanical stresses by prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclo- oxygenase (COX-2) [2, 5, 6]. Rapid production of nitric oxide (NO) is also an observed response to fluid flow, resulting from the activation of endothelial nitric oxide synthase (ecNOS), an enzyme that mediates the adaptive response of bone tissue to mechanical loading [7, 8]. Sev- eral studies have shown that the disruption of the cyto- skeleton abolishes the response to stress, implying that the cytoskeleton is involved in cellular mechanotransduction [9]. The cytoskeleton provides scaffolding for cell structure and determines the ensuing mechanical responses to forces experienced from the immediate environment. Extracellular matrix receptors, such as integrins [10, 11], form trans- membrane complex structures that are attached to the extracellular matrix as well as to the cytoskeleton. As such, R. G. Bacabac (&) Medical Biophysics Group, Department of Physics, University of San Carlos, Nasipit, Talamban, Cebu City 6000, Philippines e-mail: rgbacabac@gmail.com J. J. W. A. Van Loon Dutch Experiment Support Center, Department of Oral Cell Biology, Research Institute MOVE, ACTA-VU University, Amsterdam, The Netherlands 123 Clinic Rev Bone Miner Metab (2010) 8:179–188 DOI 10.1007/s12018-011-9082-x