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(adapted from: Bonetto and Bonewald, Basic and Applied Bone Biology, 2019)
Bone and skeletal muscle are the two largest tissues within the musculoskeletal system, which also includes tendons, ligaments, cartilage, vascular, and nervous tissue. As the major function of the musculoskeletal system is locomotion, the mechanical interactions between bone and muscle have been a singular area of research and has been investigated for decades. However, within the past few years, more attention has come to bear on the potential for molecular and biochemical interactions between these tissues, especially bone and muscle.
Independent of their mechanical interactions, it has recently been shown that bone and muscle can interact in an endocrine fashion through the production of secreted proteins and metabolites. This endocrine axis produces and releases factors that can influence other adjacent or distant tissues and organs, such as pancreas, liver, vasculature, and adipose tissue. Muscles release peptides or proteins termed “myokines” that provide a reservoir for communication with other organs in an autocrine, paracrine or endocrine manner. The importance of these myokines for human fitness and their roles in diseases, such as diabetes and obesity are beginning to emerge. Muscle factors include myostatin, leukemia inhibitory factor (LIF), Insulin-like growth factor I (IGF-1), fibroblast growth factor 2 (FGF2), and follistatin-like protein 1, IL-8 that stimulates angiogenesis, brain-derived neutrophic factor (BDNF), irisin, a potent regulator of the conversion of white fat into brown fat, and IL-15, a muscle factor that reduces adiposity. Many of these factors also have an effect on bone.
On the other hand, it has been known that bone is a ‘storehouse’ of factors within the bone matrix. The largest source of transforming growth factor beta (TGFb) in the body is in the bones along with other growth factors such as insulin-like growth factor (IGF-1) and the bone morphogenetic proteins (BMPs). These proteins are generally recognized as growth factors that can be released from the matrix by osteoclasts and enzymes such as the metalloproteases as produced by several cell types. Osteocytes produce other circulating factors such as receptor activator of nuclear factor-kappa B ligand (RANKL) and sclerostin and small molecules such as PGE2. Considering that the total cellular mass of osteocytes within the skeleton is approximately the same mass as the brain, this is a relatively large source of factors.
A partially unexplored aspect of cachexia represents the connection between loss of skeletal muscle mass and the occurrence of bone loss and osteoporosis, as often shown in patients affected with cancer or undergoing radio- or chemotherapy treatments. Observations from our group supports the idea that skeletal muscle wasting may also play a role in inducing cancer-associated bone loss, thus leading to the hypothesis that muscle and bone are regulated in tandem in cachexia. In particular, experimental and clinical observations suggest that osteoporosis, along with bone metabolism dysfunctions and the decay of bone tissue, may contribute to the pathogenesis of cachexia. Along this line, breast cancer-associated bone lesions have been shown to promote TGFb-mediated loss of muscle mass and muscle strength. Similarly, as shown in our lab, animals bearing colorectal or ovarian cancers, as well as mice administered chemotherapy regimens were showing dramatic loss of bone mass, consistently with reduced skeletal muscle mass and muscle strength.
(Andrea Bonetto 2017)
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