Muscle-bone interactions: From experimental models to the clinic? A critical update
Section snippets
Introduction: the clinical background
Bone and muscle are integrated organs with shared functions e.g. in locomotion and growth, and both may act as endocrine organs (Karsenty and Ferron, 2012, Pedersen and Febbraio, 2012). It is therefore not unexpected that development and maintenance of bone and muscle go hand in hand most of the time. Indeed, physical exercise can increase the strength and mass of muscle and bone, while both are compromised by ageing and situations of disuse like immobilization, stroke, paralysis, bed rest or
Preclinical models to study mechanical loading and disuse
Before discussing the results of studies on musculoskeletal mechanobiology in further detail, we provide here an overview of preclinical models. It is important to understand the strengths and limitations as well as caveats of different models before we discuss the lessons learned from these models.
The integrated physiology of bone and muscle
The mass and strength of bone and muscle need to be matched, both during development and maintenance. Their concerted regulation is probably determined by both genetic and environmental (e.g. nutritional) factors, either via shared control mechanisms (e.g. endocrine, nervous system regulation) or by muscle-bone crosstalk at the organ level (biomechanical signals from physical activity), cellular level (intercellular communication) or molecular level (myokines, cytokines or growth factors) (
Myostatin, activin A, their receptors, and follistatin
One of the most promising pathways for the treatment of muscle wasting disorders is inhibition of myostatin/follistatin and activin receptors. Before going into the details of how myostatin and activin A signaling induce muscle wasting and bone loss, we will first introduce this pathway and its signaling components.
Myostatin (gene MSTN, also known as growth and differentiation factor-8, GDF-8), as well as activin A and GDF-11 are members of the bone morphogenetic protein (BMP)/transforming
General conclusions
Bone and muscle have been described as “neighbors with close ties” (DiGirolamo et al., 2013), but given their inseparable function, regulation and crosstalk, we believe a metaphor of Siamese twins connected by tendons and periosteum may be more appropriate.
A third partner in this relationship, which goes beyond the scope of this review, is adipose tissue (both in fat pads as well as within bone and muscle). There is increasing awareness that obesity is not a stimulatory for bone and muscle
Acknowledgments
MRL, VD and FJ are supported by Fellowship grants from the Research Foundation Flanders (FWO). This work is supported by grant GOA/15/017 from KU Leuven and grant G.0858.11 from the Research Foundation Flanders (FWO).
MRL has received lecture fees from Flanders' Agricultural Marketing Board (VLAM) and consulted for Novartis. EG and SMPV are involved as clinical site investigators in trials with bimagrumab (Novartis). All other authors declare that they have no conflicts of interest.
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