Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors

Shi, Ce; Iura, Ayaka; Terajima, Masahiko; Liu, Fei; Lyons, Karen M.; Pan, Haichun; Zhang, Honghao; Yamauchi, Mitsuo; Mishina, Yuji; Sun, Hongchen

doi:10.1038/srep24256

Cited by 33 publications

(31 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, at 8 weeks of age, we observed the increased trabecular bone phenotype only in female in Srgap2‐cKO mice. Sex‐restricted phenotypes in genetic mouse models are not uncommon . Skeletal sexual dimorphism depends not only on androgen action in males and estrogen action in females, but also on complex sex‐specific and time‐specific interactions between sex hormones, the growth hormone/insulin‐like growth factor‐1 (GH/IGF‐1) axis, and mechanical loading.…”

Section: Discussionmentioning

confidence: 99%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The Rac1‐specific guanosine triphosphatase (GTPase)‐activating protein Slit‐Robo GAP2 (Srgap2) is dramatically upregulated during RANKL‐induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f:LysM‐Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL‐induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Mice genetically engineered to overexpress epidermal growth factor receptor ligand amphiregulin (AREG) demonstrate greater femoral BMD and total bone in the metaphyseal region at 4 and 8 weeks of age compared with WT controls, but after 10 weeks of age, there is no difference between the genotypes anymore . In addition, Shi and colleagues identified that deletion of BMP receptor BMPR1B resulted in trabecular bone loss at 8 weeks of age, which was not found either just after birth or at 11 weeks of age . Our lab also previously reported a temporal difference in skeletal changes with age between trabecular and cortical bone in DNA repair–deficient female trichothiodystrophy (TTD) mice where these mice show accelerated bone aging after 39 weeks of age .…”

Section: Discussionmentioning

confidence: 66%

Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging

et al. 2018

View full text Add to dashboard Cite

Mucin1 (MUC1) encodes a glycoprotein that has been demonstrated to have important roles in cell‐cell interactions, cell‐matrix interactions, cell signaling, modulating tumor progression and metastasis, and providing physical protection to cells against pathogens. In this study, we investigated the bone phenotype in female C57BL/6 Muc1 null mice and the impact of the loss of Muc1 on osteoblasts and osteoclasts. We found that deletion of Muc1 results in reduced trabecular bone volume in 8‐week‐old mice compared with wild‐type controls, but the trabecular bone volume fraction normalizes with increasing age. In mature female mice (16 weeks old), Muc1 deletion results in stiffer femoral bones with fewer osteoblasts lining the trabecular surface but increased endosteal mineralized surface and bone formation rate. The latter remains higher compared with wild‐type females at age 52 weeks. No difference was found in osteoclast numbers in vivo and in bone marrow osteoblast or osteoclast differentiation capacity or activity in vitro. Taken together, these results suggest that Muc1 depletion causes a transiently reduced trabecular bone mass phenotype in young mice, and later in life reduced numbers of osteoblasts with increased endocortical mineralization activity coincides with unaffected total bone mass and increased stiffness. In conclusion, our results show, for the first time to our knowledge, a role for Muc1 in bone mass and mineralization in mice in a time‐dependent manner. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

show abstract

“…5). Our in vitro cellular mechanistic studies further indicated that haploinsufficiency or even the knockout of Bmpr1b did not apparently affect cellular response to BMP ligands (Shi et al, 2016). Consistent with this, we observed that homozygous knockout of Bmpr1b did not rescue skull deformities (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 81%

BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development

Pan

Zhang

Abraham

et al. 2017

Developmental Biology

Self Cite

View full text Add to dashboard Cite

Craniosynostosis is caused by premature fusion of one or more sutures in an infant skull, resulting in abnormal facial features. The molecular and cellular mechanisms by which genetic mutations cause craniosynostosis are incompletely characterized, and many of the causative genes for diverse types of syndromic craniosynostosis have not yet been identified. We previously demonstrated that augmentation of BMP signaling mediated by a constitutively active BMP type IA receptor (ca-BmpR1A) in neural crest cells (ca1A hereafter) causes craniosynostosis and superimposition of heterozygous null mutation of Bmpr1a rescues premature suture fusion (ca1A;1aH hereafter). In this study, we superimposed heterozygous null mutations of the other two BMP type I receptors, Bmpr1b and Acvr1 (ca1A;1bH and ca1A;AcH respectively hereafter) to further dissect involvement of BMP-Smad signaling. Unlike caA1;1aH, ca1A;1bH and ca1A;AcH did not restore the craniosynostosis phenotypes. In our in vivo study, Smad-dependent BMP signaling was decreased to normal levels in mut;1aH mice. However, BMP receptor-regulated Smads (R-Smads; pSmad1/5/9 hereafter) levels were comparable between ca1A, ca1A;1bH and ca1A;AcH mice, and elevated compared to control mice. Bmpr1a, Bmpr1b and Acvr1 null cells were used to examine potential mechanisms underlying the differences in ability of heterozygosity for Bmpr1a vs. Bmpr1b or Acvr1 to rescue the mut phenotype. pSmad1/5/9 level was undetectable in Bmpr1a homozygous null cells while pSmad1/5/9 levels did not decrease in Bmpr1b or Acvr1 homozygous null cells. Taken together, our study indicates that different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development. These results also suggest differential involvement of each type 1 receptor in pathogenesis of syndromic craniosynostoses.

show abstract

Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors

Cited by 33 publications

References 44 publications

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging

BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development

Contact Info

Product

Resources

About