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Session Overview: Bone as an Endocrine Organ

As pathologists, we generally envision bone as a dynamic organ with continuous turnover and remodeling, cell death/ generation, and local and regional cell signal responsiveness. However, it is not intuitive to regard bone as equally dynamic in interorgan signaling, communicating with distant organ systems, and having a role in regulating and responding to wholebody energy metabolism, nutrient absorption/excretion, and even appetite within the central nervous system and T and B cell mediations. Yet the speakers of 4th session during the 36th annual Society of Toxicologic Pathology meeting, well-recognized experts in their field and from 3 different continents, provided illuminating talks on just this and the most current understanding in these areas. Their presentations supported that the major cells of bone—osteocytes, osteoblasts, and osteoclasts—are in continuous interplay with other organ systems including cells of the endocrine, brain, gastrointestinal, renal, and the adaptive immune systems. The first speaker, Dr. Katherine Motyl, a faculty investigator at the Maine Medical Center Research Institute, presented on Energy Metabolism of Bone, provided insight into bone cell signaling and regulation of whole-body energy metabolism. Dr. Motyl reported that one of the early indicators of the role of bone in energy metabolism was the observation that osteocalcin (OC) knockout mice were overweight, with high blood glucose, low insulin, and paradoxically concomitant insulin resistance. These findings led to the discovery that OC could directly stimulate insulin secretion and proliferation of pancreatic b cells, and insulin sensitizing adiponectin expression in adipose tissue (Lee et al., 2007). This established a signaling loop between insulin effects on osteoblast activity and osteoblast influence on insulin production by pancreatic b cells. Dr. Motyl provided evidence that other major bone cell mediators and bone signaling pathways (e.g., peroxisome proliferator-activated receptor, PPARg) regulate glucose and insulin sensitivity as well as white/brown/beige adipose tissue depots. She introduced the role of bone marrow adipose as an important source of adiponectin in systemic energy regulation as well as in bone metabolism and turnover. Her talk further covered the varying metabolic pathways that dominate ATP generation in bone cells during development, differentiation, and activity. She explained how these pathways, and pathway shifts during cell development, function (e.g., osteoclast active resorption) and the local environment (e.g., relative hypoxia for the osteocyte), determine the energy needs of bone and importance of feedback loops with systemic energy regulation. The involvement of bone within a complex regulatory network for energy homeostasis was further emphasized by the second speaker, Dr. Paul Baldock, a senior research fellow of the Osteoporosis and Bone Biology Division at Garvan Institute of Medical Research. Dr. Baldock presented on the communication networks between bone and the nervous system in his talk entitled Neuronal Control of Bone Remodeling. He noted the connectedness between both central and peripheral neural systems, and bone physiology was particularly revealed through the study of bone phenotypes in animal models with altered centrally active neuropeptide systems that regulate feeding behavior (e.g., leptin, neuropeptide Y [NPY], ghrelin, and agouti-related peptide. His talk focused on the regulatory axes and neural pathways linking these systems in the hypothalamus and brain stem with bone cells and responsive bone effects, particularly as related to the potent appetitestimulating NPY and opposing leptin systems. Evidence from experiments using a variety of models (most notably by Takeda et al. 2002) suggests the effects of leptin deficiency on cancellous bone are centrally mediated and dependent upon hypothalamic relays to (sympathetic) b-adrenergic efferent pathways which directly signal to and regulate the activity of osteoblasts. Dr. Baldock noted that conversely, centrally mediated leptin effects on cortical bone are indirect in being reflected by the absence of leptin inhibition of NPY signaling in the hypothalamus. NPY also counteracts leptin effects in being one of the most prominent orexigenic mediators and promoting