The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

Qin, Weiping; Sun, Li; Cao, Jay; Peng, Yangyang; Collier, Lauren; Wu, Yong; Creasey, Graham; Li, Jianghua; Qin, Yu; Jarvis, Jonathan C.; Bauman, William A.; Zaidi, Mone; Cardozo, Christopher P.

doi:10.1074/jbc.m113.454892

Cited by 58 publications

(69 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, glucocorticoid excess and vitamin D deficiency are catabolic, whereas androgens are anabolic to both bone and muscle (8,9). Third, we find that, in rats with experimental spinal cord injury, electrical stimulation of muscle rescues the elevated bone resorption and osteoclastogenesis in vivo, in essence providing direct evidence for muscle-bone communication, likely through a soluble molecule (10).…”

mentioning

confidence: 66%

The myokine irisin increases cortical bone mass

Colaianni

Cuscito

Mongelli

et al. 2015

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

Self Cite

415

399

View full text Add to dashboard Cite

It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity

show abstract

mentioning

confidence: 66%

The myokine irisin increases cortical bone mass

Colaianni

Cuscito

Mongelli

et al. 2015

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

Self Cite

415

399

View full text Add to dashboard Cite

show abstract

“…Interestingly, no changes in circulating osteocalcin or C-telopeptide (markers of whole body bone formation and resorption, respectively) were observed after SCI, which is somewhat inconsistent with previous reports indicating increased circulating markers of bone resorption occur in male and female rodents after spinal cord transection. 20,34 These apparent inconsistencies likely result from bone loss and (elevated) bone turnover remaining isolated to bone below the lesion level after SCI (as has been reported in humans) 36 and/or because our model differed in sex (male vs. female), age at time of injury (14 weeks vs. 6-9 weeks), and mode of injury (moderatesevere contusion SCI vs. spinal cord transection) in comparison with previous studies. 20,34 We also observed that animals subjected to SCI exhibited deleterious microstructural alterations in the shape (architecture) of the remaining trabeculae (reported as SMI) indicative of reduced plate-like architecture or increased rod-like trabecular architecture 18 and that high-dose TE prevented these changes.…”

Section: Bone Loss and Bone Turnover After Scimentioning

confidence: 73%

“…20,33,34 This bone loss is characterized by large reductions in cancellous bone mass within the first few years after SCI with cortical bone loss persisting for > 10 years. 3 Similarly, the severe cancellous bone loss that we and others 20,21,35 observed after SCI appears to have resulted from a combination of increased bone resorption, as indicated by an increased osteoclast surface, and reduced bone formation, as indicated by reduced cancellous MAR and BFR/BS.…”

Section: Bone Loss and Bone Turnover After Scimentioning

confidence: 99%

Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

Yarrow

Conover²,

Beggs

et al. 2014

Journal of Neurotrauma

View full text Add to dashboard Cite

Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.

show abstract

“…Thus, Sost-deficient mice are resistant to bone loss induced by hindlimb suspension, although the contribution of bone formation and/or bone resorption in this model remains unclear [5]. Accordingly, pharmacological inhibition of sclerostin restores bone formation in different models of microgravity, i.e., tail suspension, immobilized rats, and spine injury model [10][11][12][13]. We previously reported that down regulation of SOST and cortical bone formation in response to mechanical loading and parathyroid hormone (PTH) depends on the expression of a matricellular protein, periostin, the expression of which is increased in these conditions [14,15].…”

Section: Introductionmentioning

confidence: 94%