Characterization of Osteocrin Expression in Human Bone

Bord, S.; Ireland, Deborah C.; Moffatt, Pierre; Thomas, Gethin; Compston, Juliet

doi:10.1369/jhc.4c6561.2005

Cited by 28 publications

(32 citation statements)

References 28 publications

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“…We detected an order-of-magnitude lower production of musclin in the bone of our adult mice compared with that from skeletal muscle. This finding is consistent with original reports that indicate that high musclin expression during early bone development sharply declines in a time-and maturity-dependent manner in both mice (5) and humans (31). Furthermore, in contrast to skeletal muscle, no exercise-responsive increase in mRNA levels of musclin was observed in bones.…”

Section: Discussionsupporting

confidence: 92%

Musclin is an activity-stimulated myokine that enhances physical endurance

Subbotina

Sierra

Zhu

et al. 2015

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

146

154

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Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this study we identify musclin-a peptide with high homology to natriuretic peptides (NP)-as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca 2+ -dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption of Ostn and elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/ cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.osteocrin | mitochondria | skeletal muscle | exercise | natriuretic peptide

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Section: Discussionsupporting

confidence: 92%

Musclin is an activity-stimulated myokine that enhances physical endurance

Subbotina

Sierra

Zhu

et al. 2015

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

146

154

View full text Add to dashboard Cite

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“…CNP antagonism of the anti-proliferative effects of FGF2/FGFR3 in chondrocytes has been proposed as a mechanism through which such changes could occur (51). Interestingly, endogenous Ostn has been shown to be expressed in mature chondrocytes (52). The secreted soluble nature of Ostn would also allow its activity distal to the point of expression allowing osteoblasts adjacent to the growth plate to exert paracrine effects.…”

Section: Discussionmentioning

confidence: 99%

Osteocrin Is a Specific Ligand of the Natriuretic Peptide Clearance Receptor That Modulates Bone Growth

Moffatt

Thomas

Sellin

et al. 2007

Journal of Biological Chemistry

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Osteocrin (Ostn) is a recently discovered secreted protein produced by cells of the osteoblast lineage that shows a well conserved homology with members of the natriuretic peptide (NP) family. We hypothesized that Ostn could interact with the NP receptors, thereby modulating NP actions on the skeleton. Ostn binds specifically and saturably to the NP peptide receptor-C (NPR-C) receptor with a K d of ϳ5 nM with no binding to the GC-A or GC-B receptors. Deletion of several of the residues deemed important for NP binding to NPR-C led to abolition of Ostn binding, confirming the presence of a "natriuretic motif." Functionally, Ostn was able to augment C-type natriuretic peptide-stimulated cGMP production in both pre-chondrocytic (ATDC5) and osteoblastic (UMR106) cells, suggesting increased NP levels due to attenuation of NPR-C associated NP clearance. Ostn-transgenic mice displayed elongated bones and a marked kyphosis associated with elevated bone cGMP levels, suggesting that elevated natriuretic peptide activity contributed to the increased bone length possibly through an increase in growth plate chondrocyte proliferation. Thus, we have demonstrated that Ostn is a naturally occurring ligand of the NPR-C clearance receptor and may act to locally modulate the actions of the natriuretic system in bone by blocking the clearance action of NPR-C, thus locally elevating levels of C-type natriuretic peptide. Osteocrin (Ostn)3 is a recently discovered novel small secreted protein with prohormone-like characteristics (1). To date, the exact role of Ostn has not been elucidated. Limited homology, however, was observed between Ostn and members of the natriuretic peptide family, suggesting a possible functional link. The natriuretic system, key in the maintenance of vascular tone and cardiovascular homeostasis, consists of three related natriuretic peptides (NPs), ANP, BNP, and CNP (2) and three receptors (NPRs) mediating the biological activity of these peptides. The GC-A receptor, which preferentially binds ANP and BNP, and the GC-B receptor, whose cognate ligand is CNP, are coupled to guanylyl cyclase, producing cGMP as a secondary messenger (3, 4). The third receptor, NPR-C, has no guanylyl cyclase activity and binds all three NPs with similar affinity (5). To date, no specific endogenous ligand has been identified for NPR-C, and it is thought to act mainly as a clearance receptor (6). However, other biological functions have been postulated for this receptor (6).A number of recent reports have demonstrated that the NPs also play a key role in regulation of the skeleton (7). Mice overexpressing either BNP (8) or CNP (9) or lacking NPR-C (10) display elongated bones, whereas mice lacking CNP (11) or a functional GC-B receptor exhibit dwarfism (12). Interestingly, we initially identified Ostn in cells of the osteoblast lineage, the bone-producing cells, which together with its regulatory effects on these cells suggested a role in bone activity. Given the homology of Ostn to the NP family and its putative bone regulatory actio...

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“…Interestingly, osteocrin expression by newly formed osteoblasts is progressively inhibited over a 6-day-period by E 2 (100 pmol/l), whereas its synthesis appears to be enhanced in bone tissues taken from postmenopausal women receiving depot preparations of oestrogens (Bord et al 2005). On these grounds, differential responses of osteocrin to E 2 , based on the maturity of osteoblasts (Bord et al 2005), could underlie the abbreviated (7-day) CNP response to E 2 we observe in lambs. Bone ALP rose more promptly in the lambs and occurred on a background of decreasing levels (also observed in males, see Figs 1 and 2) as the skeleton matured.…”

Section: Discussionmentioning

confidence: 81%

“…This response contrasts with the similarly prompt but sustained elevation of both NTproCNP and CNP concentrations in the adult. Relevant here are the recent findings on osteocrin (Moffatt et al 2007) -a novel endogenous and clearance receptor-specific ligand, synthesised by newly formed osteoblasts (Thomas et al 2003) and at sites of bone remodelling in the adult skeleton (Bord et al 2005). In binding to the natriuretic clearance receptor (NPR-C), osteocrin has the potential to increase the local concentration of CNP (Moffatt et al 2007) but is unlikely to affect the concentration of NTproCNP (Prickett et al 2005, Moffatt et al 2007.…”

Section: Discussionmentioning

confidence: 98%

“…In binding to the natriuretic clearance receptor (NPR-C), osteocrin has the potential to increase the local concentration of CNP (Moffatt et al 2007) but is unlikely to affect the concentration of NTproCNP (Prickett et al 2005, Moffatt et al 2007. Interestingly, osteocrin expression by newly formed osteoblasts is progressively inhibited over a 6-day-period by E 2 (100 pmol/l), whereas its synthesis appears to be enhanced in bone tissues taken from postmenopausal women receiving depot preparations of oestrogens (Bord et al 2005). On these grounds, differential responses of osteocrin to E 2 , based on the maturity of osteoblasts (Bord et al 2005), could underlie the abbreviated (7-day) CNP response to E 2 we observe in lambs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of sex steroids on plasma C-type natriuretic peptide forms: stimulation by oestradiol in lambs and adult sheep

Prickett¹,

Barrell²,

Wellby³

et al. 2008

Journal of Endocrinology

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Although C-type natriuretic peptide (CNP) is crucial to postnatal endochondral growth, roles for the hormone in pubertal bone growth and the physiological effects of sex steroid substitution on CNP synthesis are not known. Using a plasma marker of CNP tissue synthesis (amino-terminal proCNP, NTproCNP), we have studied the effect of exogenous oestrogen (E 2 ) or testosterone (T) on plasma CNP forms and bone alkaline phosphatase (bALP) in pre-pubertal lambs.Responses to E 2 in non-cycling adult ewes were also studied. In 15-week-old intact ewe lambs, E 2 promptly increased plasma NTproCNP and CNP (P!0 . 001) to peak on day 2, and bALP (P!0 . 001 peaking on day 7), whereas no significant stimulation in response to T was observed in male lambs. Linear bone growth and live weight were unaffected. In adult anoestrous ewes, basal concentrations of CNP forms and bALP were lower than in ewe lambs, in keeping with skeletal maturity, but adults responded similarly to E 2 . Prompt and sustained increases in NTproCNP and CNP, and a later threefold rise in bALP (all P!0 . 001), were induced by E 2 . Possible contributions to these increases in plasma CNP forms by reproductive tissues (a known site of E 2 -induced CNP expression) were excluded by showing similar E 2 -induced CNP responses in adult ewes after surgical removal of reproductive tissues. These results are the first to show that E 2 stimulates plasma CNP forms and bALP in lambs and adult sheep and raise the possibility that CNP also participates in bone formation in the mature skeleton.

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Characterization of Osteocrin Expression in Human Bone

Cited by 28 publications

References 28 publications

Musclin is an activity-stimulated myokine that enhances physical endurance

Musclin is an activity-stimulated myokine that enhances physical endurance

Osteocrin Is a Specific Ligand of the Natriuretic Peptide Clearance Receptor That Modulates Bone Growth

Effect of sex steroids on plasma C-type natriuretic peptide forms: stimulation by oestradiol in lambs and adult sheep

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