Bone function, dysfunction and its role in diseases including critical illness

Abstract

The skeleton is one of the largest organs in the human body. In addition to its conventional functions such as support, movement and protection, the skeleton also contributes to whole body homeostasis and maintenance of multiple important non-bone organs/systems (extraskeletal functions). Both conventional and extraskeletal functions of the skeleton are defined as bone function. Bone-derived factors (BDFs) are key players regulating bone function. In some pathophysiological situations, including diseases affecting bone and/or other organs/systems, the disorders of bone itself and the subsequently impaired functions of extraskeletal organs/systems caused by abnormal bone (impaired extraskeletal functions of bone) are defined as bone dysfunction. In critical illness, which is a health status characterized by the dysfunction or severe damage of one or multiple important organs or systems, the skeleton shows rapid bone loss resulting from bone hyper-resorption and impaired osteoblast function. In addition, the dysfunctions of the skeleton itself are also closely related to the severity and prognosis of critical illness. Therefore, we propose that there is bone dysfunction in critical illness. Some methods to inhibit osteoclast activity or promote osteoblast function by the treatment of bisphosphonates or PTH1-34 benefit the outcome of critical illness, which indicates that enhancing bone function may be a potential novel strategy to improve prognosis of diseases including critical illness.

Figure 1

Bone-derived factors (BDFs) from bone. Bone tissue and cells can generate a variety of substances. (A) Proteins/peptides including growth factors, chemokines, cytokines, matrix protein and enzymes etc. such as FGF23, CXCL12, ILs, OC and others. (B) Matrix degradation products and metallic/non-metallic elements released during bone resorption such as CTX and lead ions. (C) Metabolic products of bone cells such as lactic acid. (D) Structural elements secreted by bone cells such as exosomes and micro vesicles.

Figure 2

Schematic diagram illustrating the effects of some molecules generated by bone on systemic homeostasis. (A) Some molecules secreted by osteoblasts, osteocytes and osteoclasts such as CXCL12, CTSK, G-CSF, MMP-9, IL-7 and IL-9 play very important roles in regulating HSCs maintenance, expansion or mobilization, and thus influence the hematopoietic and immune systems such as lymphopoiesis and megakaryopoiesis. (B) FGF23 inhibits phosphate reabsorption and promotes calcium and sodium reabsorption in the kidney. (C) GluOC and LCN2 induce insulin production and improve insulin sensitivity and then regulate energy expenditure. Sclerostin secreted by osteocytes regulates insulin sensitivity and metabolism of adipocytes. (D) GluOC promotes brain development and cognitive function. (E) GluOC can regulate male fertility by promoting testosterone production and inhibiting the apoptosis of Leydig cells in testes. (F) Bone regulates muscle mass and exercise capacity through secretion of GluOC, PGE2, VEGF, and others.

Figure 3

Bone function and hypothesis of bone dysfunction. (A) Bone function includes conventional functions (such as movement, protection and reserve of minerals) and extraskeletal functions (regulation of the function and homeostasis of extraskeletal organs/systems such as hematopoietic and immune systems, mineral and metabolism, etc.). (B) Hypothesis of bone dysfunction. In some pathophysiological situations, including genetic/aging/injury diseases of bone and/or other organs/systems diseases, the disorders of bone itself and the subsequently impaired function of extraskeletal organs/systems caused by abnormal bone (impaired extraskeletal function of bone) are defined as BONE DYSFUNCTION.

Figure 4

Schematic diagram illustrating the relationship between critical illness and bone dysfunction. Many pathological conditions such as inflammation, endocrine and metabolic disturbances, electrolyte and acid-base imbalance or vitamin D deficiency, as well as other causes such as long-term bed-rest or glucocorticoid therapies in critical illness could result in impaired osteoblast function and increased osteoclast activity, ultimately leading to acute bone loss and even bone fracture. Furthermore, the impaired osteoblast function and enhanced bone resorption could also cause increased secretion of proinflammatory factors, which might exacerbate the systemic inflammatory response. The changes of some BDFs secreted by osteoblasts such as the decreased serum levels of OC, IL-7 and CXCL12 or increased FGF23 level in critical illness may also worsen metabolic or hematopoietic disorders. We define these damages or changes in the structure and functions of bone as bone dysfunction in critical illness.