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Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1

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Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1 applied sciences Review Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1 John Kelly Smith Departments of Academic Affairs and Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, P.O. Box 70300, Johnson City, TN 37614, USA; [email protected]; Tel.: +1-423-794-7425 Received: 17 May 2020; Accepted: 24 June 2020; Published: 27 June 2020 Abstract: Astronauts at are risk of losing 1.0–1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs and diets high in nutrients, potassium, calcium, and vitamin D, all designed to preserve the skeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth factor-1 and its receptor insulin-like growth factor-1 receptor (GFR1) play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon. Keywords: Insulin-like growth factor-1; insulin-like growth factor-1 receptor; microgravity; osteoblasts; osteocytes; osteoclasts; IGF-1; IGF1R; rIGF-1; TRAIL; syncytin-A; sclerostin; bisphosphonates; romosozumab 1. Introduction All terrestrial forms of life have had millions of years to adapt to Earth’s gravity (9.8 m/sec2). Cytoskeletons constructed with actin, microfilaments and microtubules resist compressive forces and allow internal load bearing [1]. Adhesive molecules such as integrins deal with external compressive forces and allow cells to maintain their positions in space [2]. Mechanosensors shuttling between cytoplasmic membranes and nuclei and matrix clusters of cell extension kinases keep the cell informed of needed changes in gene expression [3,4]. Gravisensing organelles inform roots and stems which direction in space they should occupy [5]. And cells use thermal convection in which heated fluids rise to the top of the gravity vector and are then exchanged by cooler fluids, establishing a convection current that dissipates heat, renews nutrient supplies, and removes waste materials [6]. Nature is the ultimate architect and has done well by its creatures on Earth. But man has thrown nature a curve ball and ventured into space where all these adaptations are obsolete. The adverse effects of microgravity are particularly severe on the musculoskeletal system, particularly bone. Astronauts at are risk of losing 1.0–1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs, and diets high in nutrients, potassium, calcium, and vitamin D, all designed to preserve the skeletal system. And the adverse effects of space travel on the skeletal system may persist for years after returning to Earth. In this review, I detail the effects of microgravity on bone homeostasis and review the prominent roles that insulin-like growth factor-1 and its receptor, IGF-1R, play in the growth and maintenance this vital tissue. Appl. Sci. 2020, 10, 4433; doi:10.3390/app10134433 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 15 2. BoneAppl. Formation Sci. 2020, 10, 4433 2 of 16 In its initial phase mesenchymal stem cells and osteoblasts occupying the surface of cortical bone,2. secrete Bone Formation receptor activator of nuclear factor kappa B ligand (RANKL) which upregulates osteoclastIn differentiation its initial phase by mesenchymal binding to stem RANK cells recept and osteoblastsors on the occupying surface of the osteoclast surface of corticalprecursors. bone, This processsecrete is receptorcounterbalanced activator ofby nuclear osteoprotegerin factor kappa B(O ligandPG), (RANKL)a soluble whichdecoy upregulates receptor osteoclastthat inhibits osteoclastogenesisdifferentiation by by binding binding to RANKRANKL. receptors In the on thesecond surface phase, of osteoclast newly precursors.evolved osteoclasts This process secrete is hydrochloriccounterbalanced acid and by acid osteoprotegerin phosphatases (OPG), that a solubledegrade decoy surface receptor bone that and inhibits the bone osteoclastogenesis matrix, releasing imbeddedby binding growth RANKL. factors, In theincluding second phase,bone morpho newly evolvedgenic proteins, osteoclasts transforming secrete hydrochloric growth acidfactor- andβ and insulin-likeacid phosphatases growth factor-1. that degrade Osteoclasts surface bone form and Hows the bonehip’s matrix, lacunae releasing in trabecular imbedded bone growth and factors, a cutting zoneincluding in cortical bone bone; morphogenic once these proteins, cavities transforming reach growtha certain factor- size,β and osteoclasts insulin-like undergo growth factor-1.apoptosis, terminatingOsteoclasts bone form resorption. Howship’s lacunaeIn the third in trabecular phase boneof bone and aremodeling, cutting zone inthe cortical newly bone; liberated once these growth factorscavities stimulate reach osteoblasts a certain size, to osteoclasts evolve from undergo their apoptosis, mesenchymal terminating stem cell bone precursors resorption. to In control the third bone phase of bone remodeling, the newly liberated growth factors stimulate osteoblasts to evolve from mineralization and secrete collagen to form the bone matrix. In the fourth phase of bone remodeling, their mesenchymal stem cell precursors to control bone mineralization and secrete collagen to form osteoblasts trapped in the bone matrix evolve into osteocytes, cells that connect with one another, the bone matrix. In the fourth phase of bone remodeling, osteoblasts trapped in the bone matrix osteoblasts,evolve intoand osteocytes, osteoclasts cells through that connect a myriad with oneof dendritic another, osteoblasts, processes andthat osteoclastsconstitute through the lacunar- a canalicularmyriad network of dendritic (see processes Figures that 1 and constitute 2). Osteocytes the lacunar-canalicular are the most abundant network (see cell Figures type 1in and bone2). (90– 95% Osteocytesof all bone are cells); the most they abundant respond cell to type hormonal in bone (90–95%and mechanical of all bone signals cells); they and respond are the to primarily hormonal cell responsibleand mechanical for the signalscontrol and of bone are the homeostasis primarily cell [7,8]. responsible for the control of bone homeostasis [7,8]. RANK & M-CSF- mediated osteoclast differentiation Osteocyte Osteoclast regulation of bone mediated bone formation and resorption resorption Osteoblast Osteoblast to differentiation osteocyte bone formation differentiation and mineralization FigureFigure 1. The 1. The cycle cycle of ofbone bone formation. formation. RANK RANK and and macrophage colony colony stimulating stimulating factor factor (M-CSF) (M-CSF) signalingsignaling initiates initiates osteoclast osteoclast didifferentiationfferentiation from fr hematopoieticom hematopoietic stem cell precursors.stem cell Matureprecursors. multilobed Mature β multilobedosteocytes osteocytes resorb bone, resorb releasing bone, growthreleasing factors growth (IGF-1, factors TGF- (IGF-1,, and BMPs)TGF-β that, and initiate BMPs) osteoblast that initiate differentiation from mesenchymal stem cell precursors. Osteoblasts form and mineralize bone matrix, osteoblast differentiation from mesenchymal stem cell precursors. Osteoblasts form and mineralize and eventually evolve into osteocytes—the master regulators of bone homeostasis. bone matrix, and eventually evolve into osteocytes—the master regulators of bone homeostasis. Appl. Sci. 2020, 10, 4433 3 of 16 Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 15 Figure 2.2. A photomicrograph of an osteocyteosteocyte embeddedembedded inin itsits lacuna.lacuna. Evolved from osteoblastsosteoblasts entrapped in bone matrix, osteocytes form a multitudemultitude of dendritic extensions that communicate with osteoblasts, osteoclasts, and other osteocytes through a network of channels cut into the bone matrix. matrix. These dendritic extensions are sensitive to pressure changeschanges associatedassociated with mechanical loading and unloading and allow osteocytes to regulate the balance between bone absorption and bone bone formation. formation. Osteocytes undergo apoptosis in zero gravity, losinglosing their control over bone homeostasis, and secrete sclerostin, a mechanosensitive protein that inhibitsinhibits bone formationformation and enhancesenhances bone resorptionresorption (photograph(photograph byby SteveSteve Gschmeissner).Gschmeissner). 3. Mechanotransduction 3.1. Osteocytes 3.1. Osteocytes Exposure of osteocytes to shear stress generated in blood vessels within the Volkmann and Exposure of osteocytes to shear stress generated in blood vessels within the Volkmann and Haversian canals and interstitial fluid in the lacunar-canalicular network and in spaces between the Haversian canals and interstitial fluid in the lacunar-canalicular network and in spaces between the crystallites of the mineral hydroxyapatite and collagen fibers distorts their shape and activates the crystallites of the mineral hydroxyapatite and collagen fibers distorts their shape and activates the
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