Dominant negative Bmp5mutation reveals key role of BMPs in skeletal response to mechanical stimulation

Ho, Ayy; Marker, Paul C.; Peng, Hairong; Quintero, Andres J.; Kingsley, David M.; Huard, Johnny

doi:10.1186/1471-213x-8-35

Cited by 27 publications

(19 citation statements)

References 57 publications

(51 reference statements)

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“…Somewhat surprisingly, muscle and bone develop independently and form attachments with one another secondarily, but in a highly regulated fashion. Bone morphogenetic proteins are important, since they are required not only for skeletal patterning during embryonic development, but also for bone response to mechanical stimulation and ensuing remodeling at specific anatomic sites in the skeleton [69]. …”

Section: Relationship Between Bone and Muscle Throughout The Life Spanmentioning

confidence: 99%

Evidence for pleiotropic factors in genetics of the musculoskeletal system

Karasik¹,

Kiel²

2010

Bone

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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.

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Section: Relationship Between Bone and Muscle Throughout The Life Spanmentioning

confidence: 99%

Evidence for pleiotropic factors in genetics of the musculoskeletal system

Karasik¹,

Kiel²

2010

Bone

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“…Some of the genes are active mostly in development and others involved in homeostasis. Functional pathways regulating complex diseases are usually multigenic (Ho et al 2008;Sievänen 2005;Wolf et al 2006) since biological processes are known to be highly integrated.…”

Section: Gwas Approach For Aging Genes Discoverymentioning

confidence: 99%

“…Functional pathways regulating complex processes are usually characterized by redundancy, being regulated by multiple pleiotropic genes, seemingly to avoid perturbation triggered by the environment (Ho et al 2008;Sievänen 2005;Wolf et al 2006). Biological systems are governed by groups of genes that perform a discrete function separable from the rest of the system, called "modules."…”

Section: Pleiotropymentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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“…Drosophila decapentaplegic (DPP) and SCREW (BMP4 and BMP7 orthologs) are both required for proper spatial localization of DPP and this is proposed to be due to preferential transport of DPP/SCREW heterodimers within the embryo (11). Furthermore, mice carrying a point mutation that prevents proteolytic activation of BMP5, or humans carrying a point mutation that prevents secretion of the BMP family member growth and differentiation factor 5 (GDF5), display skeletal abnormalities that are more severe than those observed in the respective null mutants, most likely due to dominant negative effects on related BMPs that form heterodimers with endogenous BMP5 or GDF5 (12,13).…”

Section: Significancementioning

confidence: 99%

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Neugebauer¹,

Kwon

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.B one morphogenetic proteins (BMPs) are members of the TGFβ superfamily that were originally isolated as boneinducing morphogens and were subsequently found to play central roles during embryogenesis and in adult homeostasis (1). BMPs are clinically important therapeutic agents that are used to reverse bone loss caused by trauma, disease, and tumor resection (2). Their use as regenerative agents is limited, however, by their short half-life and low specific activity when implanted in vivo. Understanding how BMP activity is regulated is important for the development of more effective therapeutic agents for the treatment of bone injury and disease.BMPs bind to and activate a receptor complex consisting of type I and type II transmembrane serine/threonine kinases. Following ligand binding, activated receptors propagate their signal by phosphorylating one of the SMADs that is specific for the BMP pathway (SMAD1, -5, or -8). The phosphorylated Smads then form heterooligomers with the common Smad, Smad4, and this complex translocates into the nucleus where it binds to BMP response elements and activates transcription of target genes (1).BMPs are classified into subfamilies based on sequence homology. They signal as either homodimers, or as heterodimers from different subfamilies. For example, class I BMPs, which consist of BMP2 and BMP4, can heterodimerize with class II BMPs, consisting of BMP5-8 (3). Heterodimers composed of distinct BMP family members show a higher specific activity than do homodimers of either subunit. Homodimers of BMP2, -4, or -7, for example, can all induce bone formation, but heterodimers of BMP2 plus BMP7, or BMP4 plus BMP7 are significantly more potent (5-to 20-fold) than any of the homodimers in osteogenic differentiation assays (4-6). BMP2/7 and BMP4/7 heterodimers also sho...

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Dominant negative Bmp5mutation reveals key role of BMPs in skeletal response to mechanical stimulation

Cited by 27 publications

References 57 publications

Evidence for pleiotropic factors in genetics of the musculoskeletal system

Evidence for pleiotropic factors in genetics of the musculoskeletal system

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

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