An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia

Abstract

The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.

Influencing Factors and Molecular Pathogenesis of Sarcopenia and Osteosarcopenia in Chronic Liver Disease

“…Given that muscles and bones are closely related during their development and growth, it is conceivable that sarcopenia, osteoporosis, and osteosarcopenia often progress in conjunction with each other [ 15 , 16 , 17 , 18 ]. Therefore, an understanding of the relationship between muscles and bones along with the underlying pathogenesis of osteosarcopenia is essential from a therapeutic point of view.…”

“…Skeletal muscle cells secrete various endocrine molecules, such as IGF-1, myostatin, irisin, beta-aminoisobutyric acid (BAIBA), fibroblast growth factor 2 (FGF2), IL-6, IL-7, IL-15, and osteoglycin, which influence bone metabolism [ 15 , 16 , 17 , 18 ]. IGF-1 is synthesized primarily in the liver and is also produced by muscles and bones [ 17 ].…”

“…As bones secrete various substances that affect other organs, they may also be considered as endocrine organs. Bones secrete various osteokines such as osteocalcin, sclerostin, Wnt, TGF-β, fibroblast growth factor 23 (FGF23), and prostaglandin E2 (PGE2), which affect the metabolism of not only bones but also muscles [ 15 , 16 , 17 , 18 ]. Osteocalcin is a noncollagenous protein secreted from osteoblasts [ 116 ].…”

“…This finding has fueled the concept of osteosarcopenia, defined as the concomitant occurrence of sarcopenia and osteoporosis [ 11 , 12 , 13 , 14 ]. These two musculoskeletal disorders affect each other and share a common genetic, mechanical, and biochemical pathophysiology [ 15 , 16 , 17 , 18 ]. Osteosarcopenia has been associated with more negative health outcomes than either sarcopenia or osteoporosis alone, increasing the risk of falls, fractures, and mortality [ 19 ].…”

Obese Frailty and Combined Exercise

“…이 과정에서 발생하는 염증과 산화 스트레스는 단백질 합성 에 관여하는 mammalian target of rapamycin (mTOR)과 PI3K/Akt 경 로를 억제하고, 단백질 분해를 촉진하는 muscle RING finger protein-1 (MuRF-1)과 forkhead box proteins (FoxO)를 활성화하여 근감소증과 노쇠의 과정을 촉진한다 [44,45]. 한편, 뼈는 몸을 지탱하는 골격으로 근육의 자극을 받아 밀도를 유지하고 근육과 해부학적으로 밀접하게 연계되어 있다 [46]. 노화에 따른 근감소증과 골다공증은 서로 연계되 어 "hazardous duet"의 골근감소증으로 나타나며, 이는 낙상과 골절 위험률을 증가시켜 이동성과 독립성을 제한하는 심각한 위험으로 이 어질 수 있다 [47].…”