<i>Hox11</i> Function Is Required for Region-Specific Fracture Repair

Rux, Danielle; Song, Jane Y.; Pineault, Kyriel M.; Mandair, Gurjit S.; Swinehart, Ilea T.; Schlientz, Aleesa J.; Garthus, Kayla N; Goldstein, Steve A.N.; Kozloff, Ken; Wellik, Deneen M.

doi:10.1002/jbmr.3166

Cited by 32 publications

(27 citation statements)

References 47 publications

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“…Genetic studies have shown that Hox paralogs function redundantly in many aspects of organogenesis (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). While classically considered embryonic patterning regulators, accumulating evidence supports a continued role for Hox genes during postnatal development and adult homeostasis (17)(18)(19)(20)(21)(22)(23)(24)(25). A limitation of studying postnatal Hox function is that mutations for entire paralogous groups often lead to embryonic lethality (6-8, 14, 26-30).…”

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confidence: 99%

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hrycaj

Marty-Santos

Cebrián

et al. 2018

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

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Hox5genes (Hoxa5,Hoxb5,Hoxc5) are exclusively expressed in the lung mesenchyme during embryogenesis, and the most severe phenotypes result from constitutive loss of function of all three genes. BecauseHox5triple null mutants exhibit perinatal lethality, the contribution of this paralogous group to postembryonic lung development is unknown. Intriguingly, expression of all threeHox5genes peaks during the first 2 weeks after birth, reaching levels far exceeding those measured at embryonic stages, and survivingHoxa5single andHox5 AabbCccompound mutants exhibit defects in the localization of alveolar myofibroblasts. To define the contribution of the entireHox5paralogous group to this process, we generated anHoxa5conditional allele to use with our existing null alleles forHoxb5andHoxc5. Postnatally, mesenchymal deletion ofHoxa5in anHoxb5/Hoxc5double-mutant background results in severe alveolar simplification. The elastin network required for alveolar formation is dramatically disrupted inHox5triple mutants, while the basal lamina, interstitial matrix, and fibronectin are normal. Alveolar myofibroblasts remain Pdgfrα+/SMA+ double positive and present in normal numbers, indicating that the irregular elastin network is not due to fibroblast differentiation defects. Rather, we observe that SMA+ myofibroblasts ofHox5triple mutants are morphologically abnormal both in vivo and in vitro with highly reduced adherence to fibronectin. This loss of adhesion is a result of loss of the integrin heterodimer Itga5b1 in mutant fibroblasts. Collectively, these data show an important role forHox5genes in lung fibroblast adhesion necessary for proper elastin network formation during alveologenesis.

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mentioning

confidence: 99%

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hrycaj

Marty-Santos

Cebrián

et al. 2018

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

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“…S1A). To understand the relationship between HoxA cluster genes and the miR-23a cluster during embryonic skeletogenesis, we analyzed bone RNA for the expression of the miR-23a cluster, HoxA5, and HoxA11 during skeletal development in utero (embryonic days [12][13][14][15][16][17][18][19] and found a similar inverse relationship in expression levels (Fig. 2C).…”

Section: Mir-23a Cluster Regulates Hoxa Cluster Functionmentioning

confidence: 86%

“…Mammalian homeobox (Hox) 3 developmental transcription factors have diverse roles in bone development and postnatal bone formation (1)(2)(3). These roles include skeletal element formation (4), anterior-posterior homeotic development (4 -10), and limb and axial skeleton formation (11)(12)(13)(14)(15). In fact, cooperation among Hox genes is critical in skeletal development (2, 13, 16 -18).…”

Section: Micrornas (Mirs) and Hox Transcription Factors Have Decisivementioning

confidence: 99%

The microRNA-23a cluster regulates the developmental HoxA cluster function during osteoblast differentiation

Godfrey

Wildman

Beloti

et al. 2018

Journal of Biological Chemistry

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Edited by Joel GottesfeldMicroRNAs (miRs) and Hox transcription factors have decisive roles in postnatal bone formation and homeostasis. In silico analysis identified extensive interaction between HOXA cluster mRNA and microRNAs from the miR-23a cluster. However, Hox regulation by the miR-23a cluster during osteoblast differentiation remains undefined. We examined this regulation in preosteoblasts and in a novel miR-23a cluster knockdown mouse model. Overexpression and knockdown of the miR-23a cluster in preosteoblasts decreased and increased, respectively, the expression of the proteins HOXA5, HOXA10, and HOXA11; these proteins' mRNAs exhibited significant binding with the miR-23a cluster miRNAs, and miRNA 3-UTR reporter assays confirmed repression. Importantly, during periods correlating with development and differentiation of bone cells, we found an inverse pattern of expression between HoxA factors and members of the miR-23a cluster. HOXA5 and HOXA11 bound to bone-specific promoters, physically interacted with transcription factor RUNX2, and regulated bone-specific genes. Depletion of HOXA5 or HOXA11 in preosteoblasts also decreased cellular differentiation. Additionally, stable overexpression of the miR-23a cluster in osteoblasts decreased the recruitment of HOXA5 and HOXA11 to osteoblast gene promoters, significantly inhibiting histone H3 acetylation. Heterozygous miR-23a cluster knockdown female mice (miR-23a Cl WT/ZIP ) had significantly increased trabecular bone mass when compared with WT mice. Furthermore, miR-23a cluster knockdown in calvarial osteoblasts of these mice increased the recruitment of HOXA5 and HOXA11, with a substantial enrichment of promoter histone H3 acetylation. Taken together, these findings demonstrate that the miR-23a cluster is required for maintaining stagespecific HoxA factor expression during osteogenesis.Mammalian homeobox (Hox) 3 developmental transcription factors have diverse roles in bone development and postnatal bone formation (1-3). These roles include skeletal element formation (4), anterior-posterior homeotic development (4 -10), and limb and axial skeleton formation (11)(12)(13)(14)(15). In fact, cooperation among Hox genes is critical in skeletal development (2, 13, 16 -18). Moreover, Leucht et al. (19) reported that the Hox gene expression status influences the process of adult bone regeneration. A high-throughput ChIP-sequencing study revealed that HOXD13 binds numerous genes that act in key pathways required for early limb and skeletal patterning (20). Furthermore, Wan and Cao (21) reported that a SMAD-HOX association is required to decipher the mechanism of bone morphogenetic protein signaling in osteoblast growth and differentiation. In previous studies, we demonstrated that selective recruitment of HOX transcription factors to bone-specific chromatin at specific stages of osteoblast maturation mediates gene activation (1,(22)(23)(24). Hence, multiple levels of transcriptional and epigenetic regulation by HOX proteins must be examined to define the complete m...

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“…All results are presented as means ± standard derivations ( SD s). Due to the small sample size of n = 3 per group, power analyses between Day 8, Day 28, PN1, PN56, and/or HA comparisons were performed in nQuery Advisor Software using the Satterhwaite t ‐test . Only Raman spectroscopic results that were sufficiently powered to claim statistical significances at 80% power (two‐sided, α = 0.05) were reported in this study.…”

Section: Methodsmentioning

confidence: 99%

Bone quality assessment of osteogenic cell cultures by Raman microscopy

Mandair

Steenhuis

Ignelzi

et al. 2018

J Raman Spectroscopy

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The use of autologous stem/progenitor cells represents a promising approach to the repair of craniofacial bone defects. The calvarium is recognized as a viable source of stem/progenitor cells that can be transplanted in vitro to form bone. However, it is unclear if bone formed in cell culture is similar in quality to that found in native bone. In this study, the quality of bone mineral formed in osteogenic cell cultures were compared against calvarial bone from postnatal mice. Given the spectroscopic resemblance that exists between cell and collagen spectra, the feasibility of extracting information on cell activity and bone matrix quality were also examined. Stem/progenitor cells isolated from fetal mouse calvaria were cultured onto fused-quartz slides under osteogenic differentiation conditions for 28 days. At specific time intervals, slides were removed and analyzed by Raman microscopy and mineral staining techniques. We show that bone formed in culture at Day 28 resembled calvarial bone from 1-day-old postnatal mice with comparable mineralization, mineral crystallinity, and collagen crosslinks ratios. In contrast, bone formed at Day 28 contained a lower degree of ordered collagen fibrils compared with 1-day-old postnatal bone. Taken together, bone formed in osteogenic cell culture exhibited progressive matrix maturation and mineralization but could not fully replicate the high degree of collagen fibril order found in native bone.

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Hox11 Function Is Required for Region-Specific Fracture Repair

Cited by 32 publications

References 47 publications

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

The microRNA-23a cluster regulates the developmental HoxA cluster function during osteoblast differentiation

Bone quality assessment of osteogenic cell cultures by Raman microscopy

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