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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.

SUBMITTER: Karasik D

PROVIDER: S-EPMC4852133 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Evidence for pleiotropic factors in genetics of the musculoskeletal system.

Karasik David D Kiel Douglas P DP

Bone 20100210 5

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 musc ...[more]

PMID: 20149904

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Project description:OBJECTIVES:Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia. PATIENTS AND METHODS:We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low-density lipoproteins after dexamethasone. RESULTS:The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46×10(-215), and these variants were more likely to be in gene-regulatory regions (P=1.22×10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions. CONCLUSION:The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects.

Project description:BACKGROUND:Taping is a common treatment modality used by many rehabilitation providers. Several types of tapes and taping methods are used in the treatment of musculoskeletal dysfunction and pain. PURPOSE:To summarize and map the evidence related to taping methods used for various joints and conditions of the musculoskeletal system, and to provide clinicians and researchers with a user-friendly reference with organized evidence tables. DATA SOURCES:The PEDro, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register for Controlled Trials, PubMed, and PROSPERO databases were searched from inception through October 31, 2019. STUDY SELECTION:Eligible studies were selected by two independent reviewers and included either systematic reviews (SRs) or randomized controlled trials (RCTs) and included a musculoskeletal complaint using a clinical outcome measure. DATA EXTRACTION:Data was extracted by two investigators independently. Risk of bias and quality were assessed using A MeaSurement Tool to Assess systematic Reviews (AMSTAR) for SRs or the Physiotherapy Evidence Database (PEDro) scale for RCTs. The protocol was registered with PROSPERO (CRD42019122857). DATA SYNTHESIS:Twenty-five musculoskeletal conditions were summarized from forty-one SRs and 127 RCTs. There were 6 SRs and 49 RCTs for spinal conditions. Kinesio tape was the most common type of tape considered. Four evidence tables representing the synthesized SRs and RCTs were produced and organized by body region per condition. LIMITATIONS:Inclusion of only English language studies. Also, the heterogeneous nature of the included studies prevented a meta-analysis. CONCLUSIONS:There is mixed quality evidence of effectiveness for the different types of taping methods for different body regions and conditions. All of the SRs and RCTs found during our search of the taping literature have been organized into a series of appendices. A synthesis of the results have been placed in evidence tables that may serve as a useful guide to clinicians and researchers.

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Evidence for pleiotropic factors in genetics of the musculoskeletal system.

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Evidence for pleiotropic factors in genetics of the musculoskeletal system.

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