Bone-muscle crosstalk under physiological and pathological conditions

Abstract

Anatomically connected bones and muscles determine movement of the body. Forces exerted on muscles are then turned to bones to promote osteogenesis. The crosstalk between muscle and bone has been identified as mechanotransduction previously. In addition to the mechanical features, bones and muscles are also secretory organs which interact closely with one another through producing myokines and osteokines. Moreover, besides the mechanical features, other factors, such as nutrition metabolism, physiological rhythm, age, etc., also affect bone-muscle crosstalk. What's more, osteogenesis and myogenesis within motor system occur almost in parallel. Pathologically, defective muscles are always detected in bone associated diseases and induce the osteopenia, inflammation and abnormal bone metabolism, etc., through biomechanical or biochemical coupling. Hence, we summarize the study findings of bone-muscle crosstalk and propose potential strategies to improve the skeletal or muscular symptoms of certain diseases. Altogether, functional improvement of bones or muscles is beneficial to each other within motor system.

Keywords: Chondrogenesis; Muscle; Myokines; Obesity; Osteogenesis.

Fig. 1

The osteogenic effect depends on the origination and receptor type of IL6. (a) After the recruitment of gp130 (IL6Rβ), membrane anchored receptors (IL6Rs) combine with muscular IL6 to positively regulate osteogenesis through JAK/STAT3 signaling pathway in osteoblasts. RANKL production in OBs is also increased by muscular IL6 to mediate bone resorption. Then, more OCN released by the dynamic bone tissues functions on GPRC6A in muscles to produce more IL6. (b) Circulating IL6 binds the soluble receptors (sIL6Rs) to negatively regulate osteogenesis through SHP2/PI3K/AKT2 or SHP2/MEK/ERK signaling pathways in osteoblasts. Meanwhile, osteoclastic RANKL and PGE2 is increased to accelerate bone resorption. ERK Extracellular signal-regulated kinase, gp130 glycoprotein 130, GPRC6A G protein-coupled receptor family C group 6 member A, IL Interleukin, IL6R Interleukin 6 receptor, JAK Janus kinase, MEK mitogen-activated protein kinase-extracellular signal–regulated kinase kinase, OBs osteoblasts, OCN osteoclasts, PGE2 Prostaglandin E2, PI3K Phosphoinositide 3-kinase, RANK Receptor activator of nuclear factor-kappa B, RANKL Receptor activator of nuclear factor-kappa B ligand, SHP2 Src-homology domain 2 containing protein-tyrosine phosphatase, sIL6R soluble Interleukin 6 receptor, STAT3 Signal transducer and activator of transcription 3

Fig. 2

The role of exosomes in bone-muscle crosstalk. Exosomes are responsible for transporting noncoding RNAs between bones and muscles. Myoblasts promote osteoblastic differentiation through releasing exosomes rich in miR-27a-3p, and aging myoblasts prevent MSCs through releasing exosomes rich in miR-34a. Osteocytes release exosomes rich in miR-218 to promote OBs differentiation. Myostatin derived from muscles decreases miR-218 in osteocytes to prevent OBs differentiation. In turn, MSCs secrete exosomes rich in miR-486-5p and miR-215/miR-145-5p to positively regulate myocytes and myoblasts differentiation respectively. OBs produce exosomes rich in LncRNA TUG1 and lack in DANCR to mediate the differentiation of myoblasts. DANCR Differentiation antagonizing nonprotein coding RNA, LncRNA Long no coding RNA, MSCs Mesenchymal stem cells, OBs Osteoblasts, TUG1 Taurine upregulated 1

Fig. 3

The role of muscle derived factors and bone derived factors in bone-muscle crosstalk. Muscle derived factors such as IGF, FGF, ILs, Myostatin, Irisin, etc., regulate bone homeostasis. In turn, bone derived factors such as PGE2, FGF23, Osteocalcin, Sclerostin, Osteoactivin, etc., regulate myogenesis. FGF Fibroblast growth factor, IGF Insulin-like growth factor, IL Interleukin, PGE2 Prostaglandin E2, TMEM119 Transmembrane protein 119