Evidence for pleiotropic factors in genetics of the musculoskeletal system

Abstract

There are both theoretical and empirical underpinnings that provide evidence that the musculoskeletal system develops, functions, and ages as a whole. Thus, the risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Both bone loss (osteoporosis) and muscle wasting (sarcopenia) are the two sides of the same coin, an involution of the musculoskeletal system. Skeletal loads are dominated by muscle action; both bone and muscle share environmental, endocrine and paracrine influences. Muscle also has an endocrine function by producing bioactive molecules, which can contribute to homeostatic regulation of both bone and muscle. It also becomes clear that bone and muscle share genetic determinants; therefore the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. The aim of this review is to provide an additional evidence for existence of the tight genetic co-regulation of muscles and bones, starting early in development and still evident in aging. Recently, important papers were published, including those dealing with the cellular mechanisms and anatomic substrate of bone mechanosensitivity. Further evidence has emerged suggesting that the relationship between skeletal muscle and bone parameters extends beyond the general paradigm of bone responses to mechanical loading. We provide insights into several pathways and single genes, which apparently have a biologically plausible pleiotropic effect on both bones and muscles; the list is continuing to grow. Understanding the crosstalk between muscles and bones will translate into a conceptual framework aimed at studying the pleiotropic genetic relationships in the etiology of complex musculoskeletal disease. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both musculoskeletal conditions. This may translate into new approaches to reduce the burden of both conditions, which are prevalent in the elderly population.

Bone morphology allows estimation of loading history in a murine model of bone adaptation

“…In previous bone remodeling studies, a rather big 'lazy zone' was required to achieve more realistic results (Huiskes et al 1992), which is also in agreement with the high inhomogeneity we found in our study. Finally, it is possible that genetic or other factors play an important role when the bone structure develops and that bone in fact is only partially optimized for loading conditions (Jepsen 2009;Karasik and Kiel 2010). For example, if bone growth also takes place in the absence of loading, only part of the structure will be load adapted.…”

New Clues that May Link Osteoporosis to the Circulating Lipid Profile

“…Apart from ethnicity, a second possible confounder is represented by the existence of numerous genes shown to influence both HDLc and BMD through a pleiotropic effect (eg ABCG8, APOE, ESR1) (31). The results, in the subgroup analysis, if replicated in a larger study, would also suggest that statins protect patients with no history of previous fractures (P<0.001, r 2 =0.94).…”

Impaired skeletal health and neuromuscular function among amphetamine users in clinical treatment

“…The 13% lower lean mass in the lower extremities of the amphetamine users is in accordance with the reduced muscular strength that was observed. Loss of lean mass is usually caused by low levels of muscle activity, which has been advocated as an essential cause of age-related bone loss [41,42]. Muscle activity is mainly known to affect bone metabolism by causing mechanical strain [43].…”