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Loss of menin in osteoblast lineage affects osteocyte – osteoclast crosstalk causing osteoporosis

View Article: PubMed Central - PubMed

ABSTRACT

During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte–osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed.

No MeSH data available.


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Bone resorption is enhanced in Men1Runx2Cre mice, caused by Men1 deficiency in osteocytes. (a and b) Osteoclast numbers per bone perimeter (N.Oc/B.Pm) (a) and osteoclast surface per bone surface (Oc.S/BS) (b) in sections of femoral trabecular bone were measured by histomorphometry (n=4 or 5). (c) Determination of resorption by assessment of the serum level of the biomarker CTX in 12-week-old female Men1flox and Men1Runx2Cre mice (n=5). (d) Number of multinucleated TRAP-positive osteoclasts was counted from primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteoblasts (n=3). (e–g) Osteoclastogenesis of primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteocytes was visualized by TRAP staining (e). Number of multinucleated TRAP-positive cells (f) and their area (g) were determined (n=3). *P<0.05, **P<0.01. Data are represented as mean±S.E.M. Scale bar: 25 μm
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fig2: Bone resorption is enhanced in Men1Runx2Cre mice, caused by Men1 deficiency in osteocytes. (a and b) Osteoclast numbers per bone perimeter (N.Oc/B.Pm) (a) and osteoclast surface per bone surface (Oc.S/BS) (b) in sections of femoral trabecular bone were measured by histomorphometry (n=4 or 5). (c) Determination of resorption by assessment of the serum level of the biomarker CTX in 12-week-old female Men1flox and Men1Runx2Cre mice (n=5). (d) Number of multinucleated TRAP-positive osteoclasts was counted from primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteoblasts (n=3). (e–g) Osteoclastogenesis of primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteocytes was visualized by TRAP staining (e). Number of multinucleated TRAP-positive cells (f) and their area (g) were determined (n=3). *P<0.05, **P<0.01. Data are represented as mean±S.E.M. Scale bar: 25 μm

Mentions: We observed a strong increase of osteoclast numbers and surface in femurs (Figures 2a and b) and vertebrae (Supplementary Figures S4a and b). These increases were also seen in calvaria (Supplementary Figures S4c–e) and were associated with a high porosity (Supplementary Figure S4f). Bone resorption as determined by serum C-terminal telopeptide (CTX) level was increased in 12-week-old Men1Runx2Cre mice (Figure 2c). To test whether Men1-deficient osteoblasts could cause greater osteoclastogenesis, we performed osteoblast–osteoclast co-culture by using control or Men1-deficient osteoblasts and wild-type osteoclast precursors. Surprisingly, the Men1-deficient osteoblasts could not trigger higher osteoclast numbers (Figure 2d).


Loss of menin in osteoblast lineage affects osteocyte – osteoclast crosstalk causing osteoporosis
Bone resorption is enhanced in Men1Runx2Cre mice, caused by Men1 deficiency in osteocytes. (a and b) Osteoclast numbers per bone perimeter (N.Oc/B.Pm) (a) and osteoclast surface per bone surface (Oc.S/BS) (b) in sections of femoral trabecular bone were measured by histomorphometry (n=4 or 5). (c) Determination of resorption by assessment of the serum level of the biomarker CTX in 12-week-old female Men1flox and Men1Runx2Cre mice (n=5). (d) Number of multinucleated TRAP-positive osteoclasts was counted from primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteoblasts (n=3). (e–g) Osteoclastogenesis of primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteocytes was visualized by TRAP staining (e). Number of multinucleated TRAP-positive cells (f) and their area (g) were determined (n=3). *P<0.05, **P<0.01. Data are represented as mean±S.E.M. Scale bar: 25 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5384024&req=5

fig2: Bone resorption is enhanced in Men1Runx2Cre mice, caused by Men1 deficiency in osteocytes. (a and b) Osteoclast numbers per bone perimeter (N.Oc/B.Pm) (a) and osteoclast surface per bone surface (Oc.S/BS) (b) in sections of femoral trabecular bone were measured by histomorphometry (n=4 or 5). (c) Determination of resorption by assessment of the serum level of the biomarker CTX in 12-week-old female Men1flox and Men1Runx2Cre mice (n=5). (d) Number of multinucleated TRAP-positive osteoclasts was counted from primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteoblasts (n=3). (e–g) Osteoclastogenesis of primary co-cultures of wild-type BMCs with Men1flox or Men1gtRosaCreERT2 primary osteocytes was visualized by TRAP staining (e). Number of multinucleated TRAP-positive cells (f) and their area (g) were determined (n=3). *P<0.05, **P<0.01. Data are represented as mean±S.E.M. Scale bar: 25 μm
Mentions: We observed a strong increase of osteoclast numbers and surface in femurs (Figures 2a and b) and vertebrae (Supplementary Figures S4a and b). These increases were also seen in calvaria (Supplementary Figures S4c–e) and were associated with a high porosity (Supplementary Figure S4f). Bone resorption as determined by serum C-terminal telopeptide (CTX) level was increased in 12-week-old Men1Runx2Cre mice (Figure 2c). To test whether Men1-deficient osteoblasts could cause greater osteoclastogenesis, we performed osteoblast–osteoclast co-culture by using control or Men1-deficient osteoblasts and wild-type osteoclast precursors. Surprisingly, the Men1-deficient osteoblasts could not trigger higher osteoclast numbers (Figure 2d).

View Article: PubMed Central - PubMed

ABSTRACT

During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte&ndash;osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed.

No MeSH data available.


Related in: MedlinePlus