Ephrin B2/EphB4 Mediates the Actions of IGF-I Signaling in Regulating Endochondral Bone Formation

Wang, Yongmei; Menendez, Alicia; Fong, Chak; Elalieh, Hashem; Chang, Wenhan; Bikle, Daniel D.

doi:10.1002/jbmr.2196

Cited by 48 publications

(51 citation statements)

References 46 publications

(93 reference statements)

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“…Co-culture of differentiated primary chondrocytes from Osx1Cre.Efnb2 Δ/Δ mice showed impaired support of osteoclast formation, as we previously observed with osteoblasts derived from mice of the same genotype . This was also consistent with the work of others showing that specific inhibition of the ephrin B2-EPHB4 interaction with the TNYL-RAW peptide inhibited osteoclast formation supported by the ATDC5 chondrocyte cell line (Wang et al, 2014). Surprisingly, mRNA levels for RANKL, a ligand that supports osteoclast formation and is expressed by hypertrophic chondrocytes (Kartsogiannis et al, 1999), and for the RANKL decoy receptor OPG were unchanged.…”

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

“…Both ephrin B2 and EPHB4 are detected in proliferating and hypertrophic chondrocytes at the growth plate (Wang et al, 2014), during fracture healing (Ito et al, 2006), in articular cartilage (Othman-Hassan et al, 2001), and in the ATDC5 chondrocyte cell line (Ito et al, 2006;Wang et al, 2014). At the growth plate, ephrin B2 and EPHB4 protein levels are reported to be lower in the absence of IGF1 (Wang et al, 2014), a factor that promotes chondrocyte proliferation during longitudinal bone growth downstream of growth hormone (Sims et al, 2000). Although pharmacological inhibition of ephrin B2/EPHB4 signalling in osteoblasts promoted RANKL (also known as TNFSF11) production and support of osteoclast formation (Takyar et al, 2013), the same reagent suppressed osteoclast formation when supported by chondrocytes (Wang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…At the growth plate, ephrin B2 and EPHB4 protein levels are reported to be lower in the absence of IGF1 (Wang et al, 2014), a factor that promotes chondrocyte proliferation during longitudinal bone growth downstream of growth hormone (Sims et al, 2000). Although pharmacological inhibition of ephrin B2/EPHB4 signalling in osteoblasts promoted RANKL (also known as TNFSF11) production and support of osteoclast formation (Takyar et al, 2013), the same reagent suppressed osteoclast formation when supported by chondrocytes (Wang et al, 2014). This latter effect appeared to be independent of RANKL production (Wang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Although pharmacological inhibition of ephrin B2/EPHB4 signalling in osteoblasts promoted RANKL (also known as TNFSF11) production and support of osteoclast formation (Takyar et al, 2013), the same reagent suppressed osteoclast formation when supported by chondrocytes (Wang et al, 2014). This latter effect appeared to be independent of RANKL production (Wang et al, 2014). This suggested that ephrin B2 regulates osteoclast formation by restraining the expression of RANKL in osteoblasts but promoting a RANKL-independent action that supports osteoclastogenesis in chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

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Chondrocytic EphrinB2 promotes cartilage destruction by osteoclasts in endochondral ossification

et al. 2016

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There was an error published in Development 143, 648-657.In the Materials and Methods section the murine Efnb2 gene mutation was incorrectly listed as Efnb2 tm1And . The correct annotation for the floxed allele that we used in our experiments is Efnb2 tm2And . This was a nomenclature error and does not affect the results or conclusions of the paper.We thank Monika Tomczuk, scientific curator of Mouse Genome Informatics at The Jackson Laboratory, for alerting us to this mistake.We apologise for any confusion that this error may have caused. Osteoclasts at the growth plate had an abnormal morphology and expressed low levels of tartrate-resistant acid phosphatase; this was not observed in more mature bone. Electron microscopy revealed a lack of sealing zones and poor attachment of Osx1Cre.Efnb2 Δ/Δ osteoclasts to growth plate cartilage. Osteoblasts at the growth plate were also poorly attached and impaired in their ability to deposit osteoid. By 6 months of age, trabecular bone mass, osteoclast morphology and osteoid deposition by Osx1Cre.Efnb2 Δ/Δ osteoblasts were normal. Cultured chondrocytes from Osx1Cre. Efnb2 Δ/Δ neonates showed impaired support of osteoclastogenesis but no significant change in Rankl (Tnfsf11) levels, whereas Adamts4 levels were significantly reduced. A population of ADAMTS4 + early hypertrophic chondrocytes seen in controls was absent from Osx1Cre.Efnb2 Δ/Δ neonates. This suggests that Osx1Cre-expressing cells, including hypertrophic chondrocytes, are dependent on ephrin B2 for their production of cartilagedegrading enzymes, including ADAMTS4, and this might be required for attachment of osteoclasts and osteoblasts to the cartilage surface during endochondral ossification.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chondrocytic EphrinB2 promotes cartilage destruction by osteoclasts in endochondral ossification

et al. 2016

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Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature Osteoblasts

Babey

Wang

Kubota

et al. 2014

Journal of Bone and Mineral Research

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The primary goal of this study was to determine whether the IGF1R in mature osteoblasts and osteocytes was required for the catabolic actions of continuous parathyroid hormone (cPTH). Igf1r was deleted from male and female FVN/B mice by breeding with mice expressing cre recombinase under control of the osteocalcin promoter ((0CN) Igfr1(-/-) ). Littermates lacking the cre recombinase served as controls. PTH, 60 μg/kg/d, was administered continuously by Alzet minipumps for 4 weeks. Blood was obtained for indices of calcium metabolism. The femurs were examined by micro-computed tomography for structure, immunohistochemistry for IGF1R expression, histomorphometry for bone formation rates (BFR), mRNA levels by qPCR, and bone marrow stromal cell cultures (BMSC) for alkaline phosphatase activity (ALP(+) ), mineralization, and osteoblast-induced osteoclastogenesis. Whereas cPTH led to a reduction in trabecular bone volume/tissue volume (BV/TV) and cortical thickness in the control females, no change was found in the control males. Although trabecular BV/TV and cortical thickness were reduced in the (0CN) Igfr1(-/-) mice of both sexes, no further reduction after cPTH was found in the females, unlike the reduction in males. BFR was stimulated by cPTH in the controls but blocked by Igf1r deletion in the females. The (0CN) Igfr1(-/-) male mice showed a partial response. ALP(+) and mineralized colony formation were higher in BMSC from control males than from control females. These markers were increased by cPTH in both sexes, but BMSC from male (0CN) Igfr1(-/-) also were increased by cPTH, unlike those from female (0CN) Igfr1(-/-) . cPTH stimulated receptor activator of NF-κB ligand (RANKL) and decreased osteoprotegerin and alkaline phosphatase expression more in control female bone than in control male bone. Deletion of Igf1r blocked these effects of cPTH in the female but not in the male. However, PTH stimulation of osteoblast-driven osteoclastogenesis was blocked by deleting Igfr1 in both sexes. We conclude that cPTH is catabolic in female but not male mice. Moreover, IGF1 signaling plays a greater role in the skeletal actions of cPTH in the female mouse than in the male mouse, which may underlie the sex differences in the response to cPTH.

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Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

Wang

Menendez

et al. 2015

Journal of Bone and Mineral Research

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Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1Rflox/flox/2.3-kb α1(1)-collagen-Cre (KO) and IGF1Rflox/flox (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by μCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1α1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2α1 and collagen 10α1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb α1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair.

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Ephrin B2/EphB4 Mediates the Actions of IGF-I Signaling in Regulating Endochondral Bone Formation

Cited by 48 publications

References 46 publications

Chondrocytic EphrinB2 promotes cartilage destruction by osteoclasts in endochondral ossification

Chondrocytic EphrinB2 promotes cartilage destruction by osteoclasts in endochondral ossification

Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature Osteoblasts

Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

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