Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Fowler, Tristan W.; Kamalakar, Archana; Akel, Nisreen; Kurten, Richard C.; Suva, Larry J.; Gaddy, Dana

doi:10.1242/jcs.157834

Cited by 24 publications

(22 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As discussed above, this finding is in agreement with the increased trabecular vBMD in the distal femur observed with μCT. Activin A has been shown to induce osteoclast differentiation in vitro and in vivo [32–35], although some reports suggest a negative effect on survival and motility of mature osteoclasts [36]. The decreased osteoclast number in our study supports the role for activin A to induce osteoclast differentiation, although we cannot exclude the possible effect of other ligands binding to ActRIIB-Fc.…”

Section: Discussioncontrasting

confidence: 39%

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

Puolakkainen

Kainulainen

et al. 2017

BMC Musculoskelet Disord

View full text Add to dashboard Cite

BackgroundInhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD.MethodsThirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks.ResultsTreatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice.ConclusionsOur results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.

show abstract

Section: Discussioncontrasting

confidence: 39%

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

Puolakkainen

Kainulainen

et al. 2017

BMC Musculoskelet Disord

View full text Add to dashboard Cite

show abstract

“…Recent studies also suggest that activin A stimulation of osteoclastogenesis in vitro is mediated through stromal cells in the isolated bone marrow mononuclear cell preparation. 42 However, our data showing activin A stimulation of c-fos activation of NFATc1 through a cooperative c-fos-p-Smad2 complex is an osteoclast precursor cell-specific function. The actions of activin A on osteoclastogenesis and osteoclast function require additional study.…”

Section: Discussionmentioning

confidence: 57%

Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease

Sugatani¹,

Agapova²,

Fang³

et al. 2017

Kidney International

View full text Add to dashboard Cite

Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr−/− high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr−/− high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis.

show abstract

“…Recently, a conflicting report on osteoclast formation by activin A has been published suggesting that activin A acts as a local regulator during osteoclast development at multiple stages of osteoclast maturation by having a dominant negative effect on RANKL-stimulated osteoclast motility as well as osteoclast lifespan [100]. Interestingly, by testing whole bone marrow cultures or enriched osteoclast progenitor cultures they found enhanced RANKL-mediated osteoclast development similar to what has been described previously [89, 92, 93].…”

Section: Modulation Of Osteoclastogenesis By Activin Amentioning

confidence: 66%

“…However, activin A had no effect on stroma-free BMMs stimulated with M-CSF and RANKL, suggesting that the stimulatory effect of activin A on osteoclastogenesis is mediated by other non-macrophage like cells in the bone marrow. From their study, they claim, that activin A has no pro-osteoclastogenic effect on stroma-free BMMs, whereas activin A acts as a negative regulator of RANKL-induced osteoclast motility by activation of R-Smad2 and Akt1, which leads to activation of IκBα, a negative regulator of the NF-κB pathway [100]. …”

Section: Modulation Of Osteoclastogenesis By Activin Amentioning

confidence: 99%

Smad-dependent mechanisms of inflammatory bone destruction

2016

View full text Add to dashboard Cite

Homeostatic bone remodelling becomes disturbed in a variety of pathologic conditions that affect the skeleton, including inflammatory diseases. Rheumatoid arthritis is the prototype of an inflammatory arthritis characterised by chronic inflammation, progressive cartilage destruction and focal bone erosions and is a prime example for a disease with disturbed bone homeostasis. The inflammatory milieu favours the recruitment and activation of osteoclasts, which have been found to be the cells that are primarily responsible for bone erosions in many animal models of inflammatory arthritis. Among the inflammatory modulators, members of the transforming growth factor (TGF)-β super family are shown to be important regulators in osteoclastogenesis with Smad-mediated signalling being crucial for inducing osteoclast differentiation. These findings have opened a new field for exploring mechanisms of osteoclast differentiation under inflammatory conditions. Recent studies have shown that the TGF-β superfamily members TGF-β1, myostatin and activin A directly regulate osteoclast differentiation through mechanisms that depend on the RANKL–RANK interplay. These growth factors transduce their signals through type I and II receptor serine/threonine kinases, thereby activating the Smad pathway. In this review, we describe the impact of inflammation-induced Smad signalling in osteoclast development and subsequently bone erosion in rheumatoid arthritis.

show abstract

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Cited by 24 publications

References 59 publications

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

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

Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease

Smad-dependent mechanisms of inflammatory bone destruction

Contact Info

Product

Resources

About