Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of duchenne muscular dystrophy

Puolakkainen, Tero; Ma, Hongqiang; Pasternack, Arja; Kainulainen, Heikki; Ritvos, Olli; Heikinheimo, Kristiina; Hulmi, Juha J.; Kiviranta, Riku

doi:10.1530/boneabs.01.oc2.1

Cited by 3 publications

(4 citation statements)

References 22 publications

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“…The intimate relation between skeletal muscle and bone has been well known for more than a century . Recently, it was established that DMD is accompanied by bone fragility, which highlights the endocrinal crosstalk between muscle and bone.…”

Section: Bone Muscle Pancreas and Adipose Integrative Physiology Amentioning

confidence: 99%

Novel insights into the complex architecture of osteoporosis molecular genetics

Saad

2019

Annals of the New York Academy of Sciences

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Osteoporosis is a prevalent osteodegenerative disease and silent killer linked to a decrease in bone mass and decline of bone microarchitecture, due to impaired bone matrix mineralization, raising the risk of fracture. Nevertheless, the process of bone matrix mineralization is still an unsolved mystery. Osteoporosis is a polygenic disorder associated with genetic and environmental risk factors; however, the majority of genes associated with osteoporosis remain largely unknown. Several signaling pathways regulate bone mass; therefore, dysregulation of a single signaling pathway leads to metabolic bone disease owing to high or low bone mass. Parathyroid hormone, core‐binding factor α‐1 (Cbfa1), Wnt/β‐catenin, the receptor activator of the nuclear factor kappa‐B (NF‐κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play pivotal roles in the regulation of bone mass. The myostatin signaling pathway increases bone resorption by activating the RANKL signaling pathway, whereas osteogenic exercise inhibits myostatin and sclerostin while inducing irisin that consequentially activates the Cbfa1 and Wnt/β‐catenin bone formation pathways. The aims of this review are to summarize what is known about osteoporosis‐related signaling pathways; define the role of these pathways in osteoporosis drug discovery; focus light on the link between bone, muscle, pancreas, and adipose integrative physiology and osteoporosis; and underline the emerging role of osteogenic exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes.

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Section: Bone Muscle Pancreas and Adipose Integrative Physiology Amentioning

confidence: 99%

Novel insights into the complex architecture of osteoporosis molecular genetics

Saad

2019

Annals of the New York Academy of Sciences

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“…Systemic TGF‐β/activin inhibition with soluble decoy receptors (ACVR2A‐Fc ( 29–31 ) or ACVR2B‐Fc ( 29, 32–34 ) ) not only increased muscle mass but also increased trabecular bone volume in mice and monkeys, and further increased trabecular bone volume in Mstn‐ null mice. ( 32 ) Although the changes to bone shape, size, and mass were likely influenced by muscle hypertrophy, there is increasing evidence for direct actions of activin ligands on both osteoblasts and osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

Bone Geometry Is Altered by Follistatin‐Induced Muscle Growth in Young Adult Male Mice

et al. 2021

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“…Growth differentiation factor 8 (GDF8), commonly known as myostatin, is a member of the larger transforming growth factor β (TGFβ) superfamily of signaling ligands and functions as a potent negative regulator of muscle mass (1)(2)(3)(4)(5). Genetic deletion of GDF8 or use of GDF8 inhibitors results in a drastic increase in muscle mass (1,3,(6)(7)(8)(9)(10). In contrast, overexpression of GDF8 results in muscle atrophy (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, overexpression of GDF8 results in muscle atrophy (11)(12)(13)(14). Thus, over the last two decades significant effort has been put forth toward the development of therapies that can boost muscle mass by manipulating GDF8 signaling (8,(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

McCoy

Goebel

Thompson

2021

Biochemical Journal

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Growth differentiation factor 8 (GDF8), a.k.a. myostatin, is a member of the larger TGFβ superfamily of signaling ligands. GDF8 has been well characterized as a negative regulator of muscle mass. After synthesis, GDF8 is held latent by a noncovalent complex between the N-terminal prodomain and the signaling ligand. Activation of latent GDF8 requires proteolytic cleavage of the prodomain at residue D99 by a member of the tolloid family of metalloproteases. While tolloid proteases cleave multiple substrates, they lack a conserved consensus sequence. Here we investigate the tolloid cleavage site of the GDF8 prodomain to determine what residues contribute to tolloid recognition and subsequent proteolysis. Using sequential alanine mutations, we identified several residues adjacent to the scissile bond, including Y94, that when mutated, abolish tolloid-mediated activation of latent GDF8. Using the astacin domain of Tll1 (Tolloid Like 1) we determined that prodomain mutants were more resistant to proteolysis. Purified latent complexes harboring the prodomain mutations, D92A and Y94A, impeded activation by tolloid but could be fully activated under acidic conditions. Finally, we show that co-expression of GDF8 WT with prodomain mutants that were tolloid resistant, suppressed GDF8 activity. Taken together our data demonstrate that residues towards the N-terminus of the scissile bond are important for tolloid-mediated activation of GDF8 and that tolloid-resistant version of the GDF8 prodomain can function dominant negative to WT GDF8.

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Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of duchenne muscular dystrophy

Cited by 3 publications

References 22 publications

Novel insights into the complex architecture of osteoporosis molecular genetics

Novel insights into the complex architecture of osteoporosis molecular genetics

Bone Geometry Is Altered by Follistatin‐Induced Muscle Growth in Young Adult Male Mice

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

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