The development of therapies to treat osteoporosis based on activating the Wnt signaling pathway hold great promise. One limitation of anti‐sclerostin therapy in clinical trials is that bone formation only lasts for 2–3 months and then the anabolic effect wanes [30]. One potential explanation is that Wnt signaling induces sev- eral transcriptional targets that act as negative feedback inhibitors to blunt prolonged activation of the pathway.
One such negative feedback inhibitor, Dkk1, was shown to contribute to this blunting of response in that simulta- neous administration of antibodies that neutralized Sclerostin and Dkk1 (or exposure to a bispecific Dkk1/
Sost‐blocking antibody) resulted in an increased anabolic response [30]. Importantly, it was noted that additional feedback inhibitors were almost certainly still acting to reduce the long‐term response in this context. Thus, gaining further insight into how Wnt ligands and recep- tors are regulated may increase the efficacy of these clini- cally relevant agents and uncover additional mechanisms by which the pathway can be safely manipulated to treat osteoporosis.
ACKNOWLEDGMENTS
We apologize to any of our colleagues whose work we were unable to reference due to the strict limitations on the number of references. In many cases this necessitated citing review articles to which we refer readers for addi- tional references. Work in the Williams Laboratory is supported by the Van Andel Research Institute and by NIH/NIAMS grant AR053237.
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75
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. Edited by John P. Bilezikian.
© 2019 American Society for Bone and Mineral Research. Published 2019 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/asbmrprimer
10
INTRODUCTION
Among the most important regulators of bone shape, strength, architecture, and overall quality is the type, duration, and magnitude of mechanical loads that are placed on the skeleton. Osteocytes, which comprise 90%
to 95% of all the cells in bone, and are dispersed through
out the mineralized tissue, are the primary sensors and regulators of bone’s response to its mechanical loading environment [1]. Detection of mechanical stimuli, and transformation of mechanical signals into biochemical responses, is facilitated by the vast network of cytoplas
mic processes that extend from the osteocyte cell body throughout the lacuna–canalicular network in min
eralized bone. Cell surface molecules and structures ( integrins/cadherins, ion channels, G‐protein coupled receptors, primary cilia) and intracellular signaling path
ways (Wnt/β‐catenin, mitogen‐activated protein kinases, tyrosine kinases, cGMP/cAMP pathways) detect and transduce mechanical signals from osteocyte “sensor cells” into altered bone remodeling by “effector cells”
(osteoblasts, osteoclasts, bone lining). Several fundamen
tal processes that control skeletal adaptation to mechani
cal loading have been identified and integrated with signaling pathways, leading to a better understanding of bone tissue engineering and physiology [2], creating new opportunities for clinical/pharmaceutical and exercise strategies to promote skeletal health.