Midkine-deficiency increases the anabolic response of cortical bone to mechanical loading

Liedert, Astrid; Mattausch, Laura; Röntgen, Viktoria; Blakytny, Robert; Vogele, Daniel; Pahl, Marcus; Bindl, Ronny; Neunaber, Claudia; Schinke, Thorsten; Harroch, Sheila; Amling, Michael; Ignatius, Anita

doi:10.1016/j.bone.2010.12.019

Cited by 29 publications

(44 citation statements)

References 37 publications

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“…Furthermore, Mdk KO mice are resistant to OVX-induced bone loss and sensitive to mechanical loading induced cortical bone increase [44]. In addition, the expression of ALP and the induction of canonical Wnt signaling in MC3T3E1, an osteoblastic cell line, were inhibited by Mdk treatments [64]. These reports and the results from our current study suggest that Sostdc1 and Mdk might be responsible for a component of estrogen's osteoprotective actions.…”

Section: Discussionsupporting

confidence: 54%

“…Mdk expression is reported to increase during the course of primary osteoblast differentiation. Mdk has been shown to bind to a complex of protein tyrosine phosphatase zeta (Ptprx), low-density lipoprotein receptor-related protein-6 (Lrp6), and exert negative effects on Wnt signaling [64]. Conventional Mdk null mice exhibit increased bone formation, suggesting Mdk is a negative regulator of osteoblastic bone formation.…”

Section: Discussionmentioning

confidence: 99%

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Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice

Kondoh¹,

Inoue²,

Igarashi³

et al. 2014

Bone

102

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Estrogens are well known steroid hormones necessary to maintain bone health. In addition, mechanical loading, in which estrogen signaling may intersect with the Wnt/β-catenin pathway, is essential for bone maintenance. As osteocytes are known as the major mechanosensory cells embedded in mineralized bone matrix, osteocyte ERα deletion mice (ERαΔOcy/ΔOcy) were generated by mating ERα floxed mice with Dmp1-Cre mice to determine the role of ERα in osteocytes. Trabecular bone mineral density of female, but not male ERαΔOcy/ΔOcy mice was significantly decreased. Bone formation parameters in ERαΔOcy/ΔOcy were significantly decreased while osteoclast parameters were unchanged. This suggests that ERα in osteocytes exerts osteoprotective function by positively controlling bone formation. To identify potential targets of ERα, gene array analysis of Dmp1-GFP osteocytes sorted by FACS from ERαΔOcy/ΔOcy and control mice was performed. Gene expression microarray followed by gene ontology analyses revealed that osteocytes from ERαΔOcy/ΔOcy highly expressed genes categorized in ‘Secreted’ when compared to control osteocytes. Among them, expression of Mdk and Sostdc1, both of which are Wnt inhibitors, was significantly increased without alteration of expression of the mature osteocyte marker Sost or β-catenin. Moreover, hindlimb suspension experiments showed that trabecular bone loss due to unloading was greater in ERαΔOcy/ΔOcy mice with no loss of cortical bone. These data suggest that ERα in osteocytes has osteoprotective functions in trabecular bone formation through regulating expression of Wnt antagonists, but conversely plays a negative role in cortical bone loss due to unloading.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice

Kondoh¹,

Inoue²,

Igarashi³

et al. 2014

Bone

102

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“…Although the number of cycles required to reach 0.5 mm of displacement varied widely between animals (range: 743 to 10257 cycles), there was no significant difference between WT (6066 ± 2771 cycles) and ΔHIF-1α (4358 ± 3239 cycles) mice. For LBF loading, a 0.3 N compressive pre-load was applied followed by a cyclic rest-inserted trapezoidal waveform with a peak force of 3.0 N at 0.1 Hz for 100 cycles, similar to multi-day ulnar loading protocols used previously in the mouse [35–38]. The single loading bout protocol used here was modified from a similar procedure in rats [25], and stimulates strain-adaptive bone modeling via lamellar apposition.…”

Section: Methodsmentioning

confidence: 99%

HIF-1α regulates bone formation after osteogenic mechanical loading

Tomlinson

Silva

2015

Bone

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HIF-1 is a transcription factor typically associated with angiogenic gene transcription under hypoxic conditions. In this study, mice with HIF-1α deleted in the osteoblast lineage (ΔHIF-1α) were subjected to damaging or non-damaging mechanical loading known to produce woven or lamellar bone, respectively, at the ulnar diaphysis. By microCT, ΔHIF-1α mice produced significantly less woven bone than wild type (WT) mice 7 days after damaging loading. This decrease in woven bone volume and extent was accompanied by a significant decrease in vascularity measured by immunohistochemistry against vWF. Additionally, osteocytes, rather than osteoblasts, appear to be the main bone cell expressing HIF-1α following damaging loading. In contrast, 10 days after non-damaging mechanical loading, dynamic histomorphometry measurements demonstrated no impairment in loading-induced lamellar bone formation in ΔHIF-1α mice. In fact, both non-loaded and loaded ulnae from ΔHIF-1α mice had increased bone formation compared to WT ulnae. When comparing the relative increase in periosteal bone formation in loaded vs. non-loaded ulnae, it was not different between ΔHIF-1α mice and controls. There were no significant differences observed between WT and ΔHIF-1α mice in endosteal bone formation parameters. The increases in periosteal lamellar bone formation in ΔHIF-1α mice are attributed to non-angiogenic effects of the knockout. In conclusion, these results demonstrate that HIF-1α is a pro-osteogenic factor for woven bone formation after damaging loading, but an anti-osteogenic factor for lamellar bone formation under basal conditions and after non-damaging loading.

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“…But, in vitro assays have shown multiple ways to affect β-catenin levels without modulating WNT signaling (75). More recently in vivo knockout of factors such as Stat3(76), midkine (77), and HIF 1 α (78) have significantly modulated load-induced lamellar bone formation. It is hypothesized that each of these factors affects β-catenin levels through non-WNT mechanisms.…”

Section: Importance Of Wnt/lrp5 Pathwaymentioning

confidence: 99%

Adaptive and injury response of bone to mechanical loading

McBride¹,

Silva²

2012

BoneKEy Reports

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Bone responds to supraphysiological mechanical loads by increasing bone formation. Depending on the applied strain magnitude (and other loading parameters) the response can be either adaptive (mostly lamellar bone) or injury (mostly woven bone). Seminal studies of Hert, Lanyon, and Rubin originally established the basic “rules” of bone mechanosensitivity. These were reinforced by subsequent studies using non-invasive rodent loading models, most notably by Turner et al. More recent work with these models have been able to explore the structural, transcriptional, and molecular mechanisms which distinguish the two responses (lamellar vs. woven). Wnt/Lrp signaling has emerged as a key mechanoresponsive pathway for lamellar bone. However, there is still much to study with regard to effects of ageing, osteocytes, other signaling pathways, and the molecular regulation that modulates lamellar vs. woven bone formation. This review summarizes not only the historical findings but also the current data for these topics.

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Midkine-deficiency increases the anabolic response of cortical bone to mechanical loading

Cited by 29 publications

References 37 publications

Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice

Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice

HIF-1α regulates bone formation after osteogenic mechanical loading

Adaptive and injury response of bone to mechanical loading

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