Skeletal energy homeostasis: a paradigm of endocrine discovery

  1. William P Cawthorn1
  1. 1The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK
  2. 2The Roslin Institute, The University of Edinburgh, Easter Bush, Midltohian, UK
  1. Correspondence should be addressed to K J Suchacki; Email: ksuchack{at}
  1. Figure 1

    Bone anatomy and composition. Bone is organised into two distinct structures, cortical and trabecular. Cortical bone accounts for 80% of the skeletal mass and is highly organised, consisting of concentric lamellae arranged in Haversian systems. Trabecular, or ‘spongy’ bone, possesses ten times the surface area of cortical bone, accounting for 20% of the bone mass and enabling bone to withstand compressive and tensile forces. The bone contains osteoblasts, osteocytes and osteoclasts. Osteoblasts constitute approximately 5% of all bone cells and are the specialised ‘bone-building’ cells, originating from pluripotent mesenchymal stem cells (MSCs). Following matrix deposition and mineralisation, osteoblasts either remain on the surface of the bone as inactive lining cells; undergo apoptosis or become entombed by their secreted matrix and differentiate into osteocytes. Osteocytes reside within the mineralised bone matrix and are organised in functional syncytia collectively referred to as the osteocytic lacunar–canalicular system. Osteoclasts are derived from the haematopoietic lineage and are responsible for the resorption of mineralised bone and, in partnership with osteoblasts, regulate remodelling of bone tissue. The bone marrow further provides the haematopoietic niche, which supports the survival, self-renewal and differentiation of the haematopoietic stem cell (HSC). HSCs are capable of differentiation into two cell types: firstly, the common myeloid progenitor, which further differentiates to give rise to a number of blood cells including platelets, eosinophils, basophils, neutrophils, monocytes and erythrocytes; and secondly, the common lymphoid progenitor, which further differentiates to form B- and T-cells of the immune system. Within the bone marrow cavity, maintenance of the haematopoietic niche is orchestrated through vascular niches, which balance quiescence of HSC, proliferation and also regeneration following injury to the bone marrow. This regulation of HSC homeostasis involves intrinsic and extrinsic signals from the niche, including bound or secreted molecules, contractile force or even temperature. Haematological malignancies, or chemotherapy/radiation as a treatment for the disease, cause a limit to the regenerative and differentiation potentials of HCSs, causing a functional deficit (further discussed within text – see ‘Disease and bone’ section).

  2. Figure 2

    Regulators of bone volume, muscle mass, subcutaneous and marrow adipose tissue. (Arrow key: Red solid – increased; green solid – decreased.) Schematic representation of the key regulators of bone volume, muscle mass, subcutaneous and marrow adipose tissue. It is interesting to highlight that both calorie restriction and glucocorticoids result in the loss of adipose tissue, muscle and bone (discussed further in the text).

  3. Figure 3

    Integrative model of the regulation of the new endocrine functions bone, muscle and marrow adipose tissue. (Arrow key: black solid – accepted; black dashed – speculative; red – inhibitory.) Insulin secretion from the pancreas acts upon the insulin receptor on the osteoblast, which subsequently inhibits Forkhead box protein O 1 (FoxO1) expression and suppresses twist basic helix-loop-helix transcription factor 2 (Twist2), favouring bone resorption via osteoclast activation. The adipocyte-derived hormone leptin has been shown to have two opposing roles, acting centrally to inhibit bone mass accrual and peripherally, increasing osteoblast number and activity. The acidic pH generated in the resorption lacunae decarboxylates OCN on its three glutamic acid residues (GLU13, GLU17 and GLU20), which enable it to be released from the bone matrix into the general circulation. Once circulating, OCN can regulate global energy metabolism via the stimulation of insulin secretion and β-cell proliferation in the pancreas; energy expenditure by muscle and insulin sensitivity in adipose tissue, muscle and liver. Furthermore, OCN favours hippocampal development in offspring; brain function in adults and male fertility by stimulating testosterone synthesis in Leydig cells of the testis. A bone–muscle feed-forward axis exists where systemic undercarboxylated OCN signals to myofibres favouring uptake and subsequent catabolism of glucose and fatty acids, facilitating physical adaptation to exercise and release of exercise-induced IL-6. The latter drives the production of bioactive OCN. Adiponectin release from bone marrow adipose tissue may act to indirectly increase bioactive OCN by suppressing osteoblast proliferation, potentially favouring osteoclast activity. Another possibility is that excess local OCN production is responsible, at least in part, for elevated adiponectin production from MAT; however, this remains unclear.

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