Dissociation of Bone Resorption and Formation in Spaceflight and Simulated Microgravity: Potential Role of Myokines and Osteokines?

Abstract

The dissociation of bone formation and resorption is an important physiological process during spaceflight. It also occurs during local skeletal unloading or immobilization, such as in people with neuromuscular disorders or those who are on bed rest. Under these conditions, the physiological systems of the human body are perturbed down to the cellular level. Through the absence of mechanical stimuli, the musculoskeletal system and, predominantly, the postural skeletal muscles are largely affected. Despite in-flight exercise countermeasures, muscle wasting and bone loss occur, which are associated with spaceflight duration. Nevertheless, countermeasures can be effective, especially by preventing muscle wasting to rescue both postural and dynamic as well as muscle performance. Thus far, it is largely unknown how changes in bone microarchitecture evolve over the long term in the absence of a gravity vector and whether bone loss incurred in space or following the return to the Earth fully recovers or partly persists. In this review, we highlight the different mechanisms and factors that regulate the humoral crosstalk between the muscle and the bone. Further we focus on the interplay between currently known myokines and osteokines and their mutual regulation.

Keywords: bone formation; bone remodeling; bone resorption; disuse; space medicine; unloading.

Figure 1

Schematic illustration of the most important spaceflight health issues experienced by space travelers. The microgravity environment exerts a multitude of human health hazards (e.g., psychological effects, exposure to space radiation, immune deficiency and microgravity). Focusing on the musculoskeletal system, weightlessness conditions promote muscle atrophy as well as bone loss (I). Considering their spatially distance, it is most likely, that muscle and bone are metabolically interconnected and highly vascularized (II). Osteocytes sense external mechanical signals and transduce them into internal biochemical signals. Therefore, they are realized as the principal regulators of bone mechanosensation and mechanotransduction. Mechanical loading or unloading increases the osteocyte membrane tension which further induces the opening of PIEZO1 channels. Specifically, mechanically activated nonselective Ca²⁺-permeable cation channels of the PIEZO family (PIEZO1 and PIEZO2) are recognized as the most important mediators of mechanotransduction. SOST, a protein secreted by osteocytes is a member of the Dickkopf family, and also a potent suppressor of canonical Wnt-β-catenin signaling pathway via Lrp5/6, negatively regulates bone formation. Under weightlessness conditions, upregulation of TGF-β1 as well as RANKL has been considered as an important indicator of osteoclast activation and differentiation (III). Myokines and osteokines are released by skeletal muscle and bone tissue into the blood circulation. Microgravity therefore triggers the dissociation of bone formation and resorption (IV).

Figure 2

Myokines and osteokines produced and secreted by the skeletal muscle tissues and the bone tissues. Myokines like Irisin, IGF-1and L-BAIBA, LIF and BMP-7 positively alter the bone tissue by upregulating the activity of osteoblasts. In parallel myokines like myostatin, IL-6, IL-7 and FGF-23 stimulate bone resorption and therefore negatively regulate bone mass. Conversely, several bone cell-derived factors circulating in the periphery named osteokines influence local and systemic metabolism. They directly stimulate myogenesis and affect muscle function. Osteokines such as ucOCN, derived from bone affect skeletal muscle positively, which in turn improves muscle functions during exercise. Others such as SOST, DKK1 and RANKL effect the muscle function negatively which in turn reduces muscle function and strength.