Molecular Mechanisms of Obesity-Induced Osteoporosis and Muscle Atrophy

Abstract

Obesity and osteoporosis are two alarming health disorders prominent among middle and old age populations, and the numbers of those affected by these two disorders are increasing. It is estimated that more than 600 million adults are obese and over 200 million people have osteoporosis worldwide. Interestingly, both of these abnormalities share some common features including a genetic predisposition, and a common origin: bone marrow mesenchymal stromal cells. Obesity is characterized by the expression of leptin, adiponectin, interleukin 6 (IL-6), interleukin 10 (IL-10), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), macrophage colony stimulating factor (M-CSF), growth hormone (GH), parathyroid hormone (PTH), angiotensin II (Ang II), 5-hydroxy-tryptamine (5-HT), Advance glycation end products (AGE), and myostatin, which exert their effects by modulating the signaling pathways within bone and muscle. Chemical messengers (e.g., TNF-α, IL-6, AGE, leptins) that are upregulated or downregulated as a result of obesity have been shown to act as negative regulators of osteoblasts, osteocytes and muscles, as well as positive regulators of osteoclasts. These additive effects of obesity ultimately increase the risk for osteoporosis and muscle atrophy. The aim of this review is to identify the potential cellular mechanisms through which obesity may facilitate osteoporosis, muscle atrophy and bone fractures.

Keywords: 5-HT; AGE; IR; TNF-α; leptin; muscle atrophy; obesity; osteoporosis.

Figure 1

Obesity aided regulation of different factors and their role in bone and muscle. The up arrow “” indicates upregulation and the down arrow “” indicates downregulation and the “NS” stands for not studied.

Figure 2

Possible adverse effects of obesity on osteoblasts. (a) Anabolic pathways: Binding of BMP with BMPR induces SMAD dependent and SMAD independent pathways and ultimately transcribes the genes required for osteoblast formation. In the case of SMAD dependent signaling, activation of SMAD1/5/8 recruits SMAD4 to form a SMADs complex, which in turn transcribes particular gene/genes. SMAD 1/5/8 also activates specific genes via Osterix (Osx) mediated signaling. In case of SMAD independent signaling, activated BMPR induces the transcription factor runt-related transcription factor 2 (RUNX2) and activator protein 1 (AP1) to be activated through P³⁸MAPK/JNK/ERK signaling pathway. Obesity inhibits BMP signaling by upregulating the expression of some BMP inhibitors like MGP, Noggin, SOST, and Gremlin. TGF-β/Activin may activate several receptor subtypes including ACVRIIA, ACVRIIB, ACVRIB, and ACVRIC. Like BMP signaling, Activin also signals through SMAD dependent and SMAD independent pathways, but the main difference is that Activin induces SMAD2/3 and then recruits SMAD4 to form a SMADs complex. Obesity decreases Activin signaling via upregulating the expression of follistatin-like 1 (FSTL1), a potential inhibitor of Activin signaling. Binding of canonical with Frizzled/Lipoprotein receptor-related proteins (FZD/LRPs) complex activates vessel dilator (VDL), which in turns prevents β-catenin (β-cat) degradation as well as subsequent translocation of β-cat into the nucleus to activate T cell factor/lymphoid enhancer factor (TCF/LEF) by sequestering Glycogen synthase kinase 3 β (GSK3β). Binding of non-canonical Wnt with FZD triggers three different signaling pathways: (1) FZD recruits LRP and disheveled associated activator of morphogenesis 1 (DAAM1) to form a complex, which in turns activates the gene via RHO/ROCK/NFATC1 signaling pathway; (2) VDL forms a complex with Rac to activate RUNX2 via c-Jun NH₂-terminal kinase (JNK) activation; and (3) Activated FZD induces the activation of G protein, which in turn activates Phospholipase C (PLC) to generate inositol-1,4,5-trisphosphate (IP3) to increase the cytosolic Ca²⁺ concentration and these Ca²⁺ act as negative regulators of peroxisome proliferator activated receptor γ (PPAR-γ). Obesity decreases Wnt signaling by upregulating the expression of Wnt inhibitors like SOST and Dickkopf Wnt Signaling Pathway Inhibitor 1 (DKK1). Upon activation of IGF-1 receptor (IGF-1R) by I/IGF-1 transcribes the corresponding genes through PI3K/AKT signaling and MAPK signaling pathways. Activated protein kinase B (AKT) also inhibits Forkhead box O1 (FOXO1) and GSK3β resulting in decreased expression of negative regulatory elements. Obesity-induced insulin resistance (IR) decreases I/IGF signaling. (b) Catabolic pathways: Decreased level of 5-HT from the brain suppresses bone formation by facilitating the activation of β2 adrenergic receptor (Adrβ2), which transcribes Cyclin D1 (CycD1) inhibitory factor through PKA/ATF4 signaling pathway. Adrβ2 also upregulates the expression of receptor activator of nuclear factor kappa-β ligand (RANKL) through an unknown pathway. Obesity is inversely related to brain 5-HT_2CR expression. PTH signaling has both positive and negative impacts on osteoblast development. Activated parathyroid hormone 1 receptor (PTH1R) induces the activation of G protein, which in turn activates positive regulatory elements via cAMP/PKA/CREB signaling pathway although cAMP response element binding protein (CREB) requires the recruitment of FOXO1 to be activated. PTH1R also inhibits Activin/TGF-β signaling by inhibiting the Activin receptor (ACVR). Obesity causes the elevation of PTH via decreasing vitamin D synthesis. Duodenal 5-HT decreases PTH signaling by inhibiting protein kinase A (PKA) as well as preventing the recruitment of FOXO1 with CREB resulting in decreased osteoblastogenesis. Obesity upregulates duodenal 5-HT expression. GC binds with the glucocorticoid receptor (GR) to form the GC-GR activation complex, which induces osteoblast apoptosis through GSK3β/P³⁸ signaling, generation of reactive oxygen species (ROS) by endoplasmic reticulum (ER) stress and via activation of caspase 3/9 (Csp3/9). In addition, GSK3β inhibits β-cat activity and ROS inhibits Nuclear factor-like 2 (Nrf2), a positive regulator of osteoblast. Sometimes GC activates the positive regulatory elements too. Excess GC uptake is associated with obesity. IL-6 induced JAK/STAT3 signaling has both positive and negative effects on osteoblast. In addition, IL-6 exerts its negative role via SHP2/PI3K/AKT signaling and via SHP2/MEK2/ERK signaling pathways. Obesity induces IL-6 upregulation through increased generation of Ang II, AGE and leptin. TNF-α activated TNF receptor (TNFR) activates nuclear factor-κB (NF-κB), which has both negative and positive roles in osteoblastogenesis. Obesity is responsible for increased synthesis of TNF-α.

Figure 3

Possible adverse effects of obesity on osteoclast. Upon binding of RANKL with the receptor activator of nuclear factor kappa-β (RANK) activates the adaptor protein TNF receptor-associated factor 6 (TRAF6), which thereby activates the transcription factor NFATC1 via three different signaling pathways: (1) MAPK/AP1 mediated (2) IKK/NF-κB mediated, and (3) Rac/ROS/PLCγ/Ca²⁺/calcineurin mediated. Obesity induces RANKL signaling by decreasing the production of osteoprotegerin (OPG), a RANKL antagonist. IL-6 induces IL6R activation and thereby positively regulates the osteoclastic gene by the JAK/STAT signaling pathway. Binding of MCP1 with the C-C motif chemokine receptor 2 (CCR2) induces osteoclasogenesis via JAK/STAT and Ras/MAPK signaling pathways. TNF-α activates TNF receptor 1 (TNFR1) and this activation leads to recruits TNFRSF1A associated via death domain (TRADD) and Receptor-Interacting Protein 1 (RIP1) with TNFR1 and this complex thereby activates TRAF2/5/6, which in turn activates the specific gene via IKK/NF-κB and MAPK mediated signaling pathways. M-CSF activates NFATC1 through PI3K/AKT/NF-κB mediated signaling pathway or induces the activation of transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and hypoxia-inducible factor 1-alpha (HIF1α) through the PI3/AKT/mTOR signaling pathway. Obesity is associated with increased expression of IL-6, TNF-α, MCP1, and M-CSF.

Figure 4

Possible antagonistic effects of obesity on myocyte signaling to accelerate muscle atrophy. (a) Anabolic pathways: IGF signaling is the main anabolic signaling pathway in the myocyte. Binding of I/IGF with their receptor (IR) activates IR, which in turn activates AKT through successive activations of IRS, PI3K and PDK1. Activated AKT, then in turn activates mTOR and NF-κB as well as inhibits FOXO and GSK3β. mTOR is a positive regulator of muscle because it induces the synthesis of muscle proteins and inhibits proteolysis by activating S6 kinase beta-1 (S6K1), whereas both FOXO and GSK3β are negative regulators of muscle because FOXO is a transcription factor that upregulates the transcription of E3 ubiquitin ligases and GSK3β inhibits both eIF2B and nebulin. Activated IR also inhibits Csp3 functioning through inducing the activation of cellular inhibitor of apoptosis protein 1 (cIAP1) and MAPK/ERK kinase (MEK). Leptin signaling is another anabolic signaling pathway that induces muscle protein synthesis through the JAK2/STAT signaling pathway induced by activated leptin receptor long isoform (LEPRb). Activated JAK2 may induce I/IGF signaling via the activation of IRS. (b) Catabolic pathways: Binding of GC with GR in cytosol forms the GC-GR complex and translocates into the nucleus where it induces the transcription of FOXO1, Atrogin-1, and MuRF-1 through binding with the respective genes. GC signaling also induces the upregulation of Kruppel-like factor 15 (KLF15), regulated in development and DNA damage responses -1 (REDD1) and pyruvate dehydrogenase kinase 4 (PDK4). Both KLF15 and REDD1 inhibit protein synthesis in muscle by sequestering mTOR and by inducing FOXO activation (by KLF15). PDK4 reduces glucose oxidation. IL-6 signals through the IL6R/JAK/STAT pathway and induces the overexpression of the suppressor of cytokine signaling-3 (SOCS3), a negative regulator of muscle. Myostatin induced activated ActRIIB signals through the SMAD2/3 dependent pathway and induces the expression of some proteins which downregulate the expression of MyoD and myogenin. Myostatin also induces the upregulation of atrogin1 and MuRF1 through the activation of FOXO. AGE induces the expression of Csp3 through the RAGE/P³⁸MAPK signaling pathway resulting in apoptosis of myocytes. The active receptor for advanced glycation end products (RAGE) also induces the generation of ROS by activating the enzyme, NADPH oxidase. This ROS can induce the expression of Bnip3 through the activation of FOXO, and also activates NFκB via the MAPK-JNK/p³⁸/ERK1/2 signaling pathway. Ang II induced activation of ATR1 triggers the generation of ROS, which in turn upregulates the expression of MuRF1 via IKK/NF-κB mediated signaling and also accelerates proteolysis via Csp3 activation. Ang II signaling downregulates IGF signaling by suppressing IRS1 and also inhibits mitochondrial biogenesis. TNF-α induces the expression of iNOS, Murf1, and Atrogin1 through NF-κB and P³⁸/MAPK mediated signaling pathway. Active TNFR also inhibits IRS via JNK activation and ultimately downregulates IGF signaling. Sarcomeric protein derived AMP also activates AMPK, that in turns activates FOXO, induces mitochondrial fatty acid (FA) oxidation to generate ROS and inhibits mTOR. PTEN acts as a negative regulator of I/IGF signaling by sequestering IRS. (c) Obesity negatively regulates the anabolic pathways and positively regulates the catabolic pathways, ultimately causing muscle atrophy.

Figure 5

Possible pathways of obesity-induced osteoporosis and bone fractures.