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Emerging Insights into the Role of the Skeleton
Unexpected functions for the skeleton have emerged in the past few years, indicating it plays a key role in whole-organism physiology. Not always appreciated as a dynamic tissue, the skeleton is very active, renewing itself in the adult approximately every 10 years.
The skeleton has three main cell types: the bone-forming cell (the osteoblast), the bone-resorbing cell (the osteoclast), and the least known but most abundant cell, the osteocyte, which forms a network throughout bone tissue, linking cells via a dendritic network. The osteocyte acts as a mechanical transducer, converting mechanical strain (e.g., during walking or jumping) to biochemical messages that orchestrate bone-cell activity.
Bone’s relationship with the reproductive system is well established and has been the long-term focus of research linked primarily to postmenopausal osteoporosis and more recently with male osteoporosis and androgen-deficiency. Most osteoporosis therapies are anti-resorptive drugs directed at preserving bone or reducing bone loss. Because they are highly effective and specific for bone, these potent agents—for example the recently approved denosumab—are not only indicated for postmenopausal osteoporosis in women at high risk of fracture but also as a treatment in men to increase bone mass in patients who are at high risk of fracture from receiving androgen-deprivation therapy (for nonmetastatic prostate cancer) or adjuvant aromatase inhibitor therapy (for breast cancer).
The skeleton also interacts with many other systems. An important relationship between bone and the immune system is becoming clearer as we understand the regulation of key pathways involved in cell differentiation, since cells of the monocyte lineage differentiate into macrophages, myeloid dendritic cells, microglia, or osteoclasts. In chronic inflammatory disease, for example, Th1 cells stimulate osteoclast formation while Treg cells (Th-17) suppress osteoclast formation, establishing clear links between the immune system and bone.
A role for estrogen to prevent bone loss by regulating T-cell function has also been established in preclinical models. By understanding the crosstalk between bone and the immune system, researchers are uncovering the mechanism by which sex steroids, infection, and inflammation lead to bone loss by disregulating T-cell function.
Other systems, however, such as the link between energy metabolism, the brain, and bone mass are not quite as evident. There is evidence to suggest a central control of energy metabolism through the hypothalamic-leptin (a fat hormone) pathway. On the other hand, there is also evidence of the skeleton’s role as an endocrine organ regulating energy metabolism on a global level. For example, leptin serves as an adiposity signal to inform the brain about fat mass to regulate food intake and energy expenditure. Leptin also plays important roles in angiogenesis, immune function, fertility, and bone formation, linking it to several systems.
Link to Metabolism
Several labs have focused on the interactions between bone and fat and the control of energy metabolism in the last few years (Karsenty and Clemens), providing new insight as to how the skeleton acts as an endocrine organ. Osteocalcin, a bone-formation marker secreted by osteoblasts, has been identified as one of possibly several bone-derived hormones that have been shown to modify insulin production and sensitivity and to boost energy expenditure.
Antidiabetes and anti-obesity drug classes acting through PPAR activation to influence glucose metabolism and affect insulin secretion/production also have reported effects on bone. These include the PPAR gamma agonists TZD’s, FGF21, or PPAR alpha agonists. The effects on the skeleton vary depending on age and existing bone quality, and it will be interesting to learn how the newer drug classes affect bone health.
New diabetes treatments control glucose levels in several ways, including compounds that increase pancreatic glucose utilization and production (glucokinase activation), stimulate the selective renal excretion of glucose (SGLT1/2 inhibitors), or sensitize pancreatic beta cells to glucose levels and suppress appetite (GLP-1/DPD-4 inhibitors). As we gain in our understanding of the important interactions between bone and energy metabolism there is potential to design drugs with dual function, hopefully to treat diabetes and also protect the skeleton.
Relationship to Muscle
Skeletal interactions with muscle are also worth noting. A close functional and developmental relationship between bone and muscle has been appreciated for decades, which is not too surprising given their physical proximity and common cell origin and function (osteoblasts, adipocytes, myocytes, and chondrocytes are all derived from the same mesenchymal cell precursors).
The muscle-bone relationship is largely mechanical—driven by contractile muscle forces on bone—and important for maintaining bone health. However, there is evidence that muscle tissue itself acts as an endocrine organ, secreting a wide variety of growth factors and cytokines that may have the potential to alter bone metabolism.
Integrating muscle and bone biology to provide a multidisciplinary approach to research facilitates our understanding of the mechanism of action of emerging new targets in drug development, especially those designed to treat age-related muscle-wasting disorders and devastating childhood diseases such as Duchenne muscular dystrophy. Regulatory agencies are requesting comprehensive testing of new therapeutics intended for juvenile or young adult populations in order to evaluate the effects of a compound on the growing skeleton and ensure its safety.
Finally, there is a growing appreciation for the fact that many bone cell-signaling pathways are common to other cell types, and therefore therapeutics targeting a specific pathway may have off-target or downstream effects on bone, adding to the complexity of drug development and safety testing.
We lose weight: we lose bone; we build muscle: we build bone; we become diabetic: bones become fragile. Bone fragility and treating the consequences of fracture is a major public health concern costing millions of annual tax dollars, underscoring the need to ensure that nutraceuticals and pharmaceuticals are safe or beneficial for the skeleton.
Susan Y. Smith is a senior scientific director at Charles River. To learn more about Charles River science, please visit Eureka.
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