The skeletal subsystem as an integrative physiology paradigm.
Homeostatic bone remodeling depends on precise regulation of osteoblast-osteoclast coupling through intricate endocrine, immune, neuronal, and mechanical factors. The osteoblast-osteoclast model of bone physiology with layers of regulatory complexity can be investigated as a component of a local skeletal subsystem or as a part of a complete whole-body system. In this review, we flip the traditional investigative paradigm of scientific experimentation ("bottom-top research") to a "top-bottom" approach using systems biology. We first establish the intricacies of the two-cell model at the molecular signaling level. We then provide, on a systems level, an integrative physiologic approach involving many recognized organ-level subsystems having direct and/or indirect effects on bone remodeling. Lastly, a hypothetical model of bone remodeling based on frequency and amplitude regulatory mechanisms is presented. It is hoped that by providing a thorough model of skeletal homeostasis, future progress can be made in researching and treating skeletal morbidities.
Weiss
Aaron J
AJ
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Iqbal
Jameel
J
Zaidi
Neeha
N
Mechanick
Jeffrey I
JI
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology; D016207:Cytokines / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D010011:Osteocytes / Q000502:physiology; D010281:Parathyroid Hormone / Q000502:physiology; D053245:RANK Ligand / Q000502:physiology; D013972:Thyrotropin / Q000502:physiology
D016207:Cytokines; D010281:Parathyroid Hormone; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D013972:Thyrotropin
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