Musculoskeletal Mechanobiology: A New Era for MechanoMedicine X. Edward Guo, 1 Clark T. Hung, 1 Linda J. Sandell, 2 Matthew J. Silva 2 1 Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY 10027, 2 Department of Orthopaedic Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110 Published online 27 October 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.23789 Biomechanical factors are of fundamental and recog- nized importance in regulation of the musculoskeletal system. For instance, conditions such as osteopenia/ osteoporosis, osteoarthritis, tendinopathy, muscle at- rophy, and intervertebral disc degeneration are asso- ciated in part with aberrant mechanical loading signals to the cells that reside in these load-bearing connective tissues. Most musculoskeletal disorders, in general, alter tissue form and function over time through changes in contractile force and geometry of single cells. While it is understood that mechanical actions are at play, we have only begun to understand how mechani- cal forces are sensed and interpreted. Elucidation of the underlying mechanisms of cell mechanotransduction will provide insights to the etiology of disease, tissue maintenance as well as development of new treatment strategies. The latter will permit optimization, for instance, of the therapeutic benefits of periodic mechan- ical stimulation on enhanced fracture healing as well as exercise regimens for preventing bone loss. Recent discoveries showing that extracellular ma- trix mechanics alone can modulate and control stem cell differentiation have positioned mechanobiology at the cusp of MechanoMedicine, that is, mechanobiology clinically relevant to orthopaedic medicine and to musculoskeletal health. Mechanical cues can not only modulate cell differentiation or gene expression, but they can also cause epigenetic modifications of the genome itself. This is an important example of the functional consequences of mechanical influences on genetic control. The study of mechanobiology is a daunting scientific problem that transcends cell and tissue type and intrinsically spans the multiple scales of biological systems: Molecules, cells, tissues, organs, and whole organisms. The application of modern molecular biology, imaging, and computational tech- nologies by multidisciplinary researchers will provide untold opportunities to tackle this enormously chal- lenging, complex and multiscale problem. It is timely now to review the current state of the art and status of musculoskeletal mechanobiology in the field. Most importantly, we need to develop a grand vision on how to translate our increasing understand- ing of mechanobiology to clinical breakthroughs in preventing/treating critical musculoskeletal disorders using MechanoMedicine. With this goal in mind, we are pleased to introduce this special issue in Musculoskele- tal Mechanobiology. This special issue begins with several outstanding reviews that provide updates on the significance of mechanobiology in musculoskeletal research involving cartilage, tendon, muscle and bone, 1–10 and that span topics from the role of candi- date mechanosensors and chemical mediators, 1,5,9,10 in vitro and in vivo models of tissue injury and repair, 3,4 and supporting technologies. 6,7 The majority of original articles following the review papers are related to the mechanobiology of bone and cartilage, 8–23 tissues whose physical regulation have traditionally garnered inten- sive research focus, followed by complementary re- search papers in areas of growing prominence: Ligaments, intervertebral discs, and stem cells. 24–28 From this Special Issue in Musculoskeletal Mecha- nobiology, it is clear that it has become technically possible to trace the impact of mechanics from individ- ual molecules to an entire organism. With this capabil- ity, mechanobiology is entering a new phase where basic science melds with translational medicine, one that can inspire new therapeutic treatments and pharmaceutical interventions in the clinical arena. By elaborating the role of mechanics within and across biology and physiology with engineering innovations, we envision increasing clinical impact as musculoskel- etal mechanobiology sets the stage for a future of Orthopaedic MechanoMedicine. REFERENCES 1. Moore ER, Jacobs CR. 2017. The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development. J Orthop Res 36:533–545. 2. Gibbons MC, Singh A, Engler AJ, et al. 2017. The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration. J Orthop Res 36:546–556. 3. Thampatty BP, Wang JHC. 2017. Mechanobiology of young and aging tendons: in vivo studies with treadmill running. J Orthop Res 36:557–565. 4. Wang T, Chen P, Zheng M, et al. 2017. In vitro loading models for tendon mechanobiology. J Orthop Res 36:566–575. 5. Tian F, Wang Y, Bikle DD. 2017. IGF-1 signaling mediated cell-specific skeletal mechano-transduction. J Orthop Res 36:576–583. 6. Li Z, Muller R, Ruffoni D. 2017. Bone remodeling and mechanobiology around implants: insights from small ani- mal imaging. J Orthop Res 36:584–593. Correspondence to: X. Edward Guo, (T: (212) 854-6196; F: (212) 854-8725; E-mail: exg1@columbia.edu); Clark T. Hung, (T: (212) 854-6542; F: (212) 854-8725; E-mail: cth6@columbia.edu); Matthew J. Silva, (T: 314-362-8585; F: 314-362-0334; E-mail: silvam@wustl.edu) # 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. JOURNAL OF ORTHOPAEDIC RESEARCH 1 FEBRUARY 2018 531