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 whole-body 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 β 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 β cells. Dr. Motyl provided evidence that other major bone cell mediators and bone signaling pathways (e.g., peroxisome proliferator-activated receptor, PPARγ) 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 appetite-stimulating 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) β-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 conservation of energy expenditure that supports anabolic effects on peripheral adipose tissue. Hence, the effects of NPY and leptin are interrelated and complex in their effects on bone/bone type. He further indicated future areas of research interest including the role of osteoblast-derived lipocalin 2 and osteoglycin in bone–neural and hormonal networks.

The third session speaker, Dr. Reinhold G. Erben, a physician, veterinarian, and professor of physiology and pathophysiology at University of Veterinary Medicine, Vienna, Austria, focused specifically on such bone–hormonal networks in his presentation on Pleiotropic Actions of FGF23. He noted that fibroblast growth factor 23 (FGF23) is a bone-derived hormone produced mainly by osteocytes and osteoblasts with secretion stimulated by systemic increases in vitamin D and extracellular phosphate. Dr. Erben’s research has shown that FGF23 is an autocrine/paracrine suppressor of alkaline phosphatase transcription in bone, thereby inhibiting local mineralization and contributing to impaired bone mineralization in diseases associated with increased FGF23. However, he centered his talk on the role of FGF23 as a bone-derived endocrine mediator interacting with multiple other organ systems (particularly renal, intestinal, cardiovascular, and immune). FGF23 signaling in renal tissues including through α-Klotho-dependent Fibroblast Growth Factor Receptor 1 (FGFR1) leads to decreased renal proximal tubular phosphate and increased distal tubular sodium and calcium absorption. FGF23 signaling in the kidney and other organs leads to decreased circulating active vitamin D (via suppressed enzyme formation and enhanced enzyme catabolism) and consequently decreased intestinal phosphate and calcium absorption. Dr. Erben detailed some of the key studies conducted that revealed FGF23 signaling pathways in the kidney and effects of increased FGF23 such as with chronic kidney disease (CKD), emphasizing the implications for overall disease progression. For example, FGF23-mediated sodium reabsorption in the kidney may have a role in blood volume and pressure regulation and contribute to the link between blood FGF23 levels and adverse outcomes with CKD and worsening prognosis following cardiovascular events. Dr. Rheinhold also covered recently reported pathological effects of increased FGF23 with cardiac conditions (clinical left ventricular hypertrophy or experimental myocardial infarction) and in the host defensive immune response through Klotho-independent suppression of leukocyte recruitment to inflamed tissues.

The fourth speaker of the session, M. Neale Weitzmann, professor of medicine at Emory University School of Medicine, presented more specifically on the immune–skeletal interface, unfolding how the immune system mediates powerful effects on bone in a talk entitled Bone and the Immune System. Dr. Weitzmann spoke of the role of the adaptive immune system as an important supporting element in bone homeostasis in health, and conversely, contributing to bone loss and osteoporotic progression in altered immune states. Dr. Weitzmann listed the cytokines and chemokines most associated with osteoporosis and emphasized osteoclasts as important responders to these and other pro-inflammatory signals in triggering the imbalance in bone resorption over formation. In particular, osteoclast activity is driven by their development from myeloid monocyte–lineage cells promoted by the binding of their surface receptor activator of Nuclear Factor (NF)-κB (RANK) with the Tumor Necrosis Factor (TNF) superfamily member ligand (RANKL). The osteoclast-stimulating RANKL is produced by a variety of cell types but particularly by inflammation-activated T and B cells. Directly opposing the pro-osteoclast development of RANKL is a functional decoy receptor, osteoprotegerin (OPG) that is also produced by a variety of cell types but especially B lineage cells in the physiologic resting state. Dr. Weitzmann’s lab has shown that the most significant source of OPG in healthy mice were mature B cells in the bone marrow. In addition, through Cluster of Differentiation (CD)40 ligand (CD40L), T cell activation of B cell CD40 can upregulate B cell OPG production in peripheral tissues. Therefore, both B and T cells are involved in the production of the protective RANKL-decoy OPG in health. Correspondingly, published results indicate that the ratio of RANKL/OPG in the osteoclast precursor environment serves as a key indicator of bone loss potential. Dr. Weitzmann noted the utility in the shift in this RANKL/OPG ratio, with consideration of other potent pro-inflammatory mediators such as TNFα from activated (including T and B) cells in understanding the role of the immune system in bone loss. He provided results and background understandings from his and other research laboratories showing immune system effects on bone in patients with HIV and antiretroviral therapy, the transgenic (HIV-1Tg) rat model, studies of rheumatoid arthritis with the anti-CTLA4 therapeutic abatacept, and models of estrogen deficiency osteoporosis. He also introduced how bone itself may regulate immune responses.

In summary, this session 4 of the STP meeting presented important information showing bone as a highly interactive organ intricately connected with other systemic signaling pathways of the body. The talks generated useful audience questions and discussion and opened eyes on how effects on these whole-body systems—metabolic, endocrine, neural, and immune—could be implicated in bone (and bone biomarker) changes and vice versa. These learnings aligned with our current understanding of bone in a toxicology setting (Smith, Varela, and Samadfam 2017). The connectedness of bone with other body systems on a molecular, cellular, and systemic level via paracrine, endocrine, neurologic, and combined interactions was both fascinating and incredibly pertinent to the drug safety work many of us do every day.