Scaling of Haversian canal surface area to secondary osteon bone volume in ribs and limb bones

Authors

John G. Skedros, Alex N. Knight, Gunnar C. Clark, Christian M. Crowder, Victoria M. Dominguez, Shijing Qiu, Dawn M. Mulhern, Seth W. Donahue, Björn Busse, Brannon I. Hulsey, Marco Zedda, Scott M. Sorenson

Abstract

Studies of secondary osteons in ribs have provided a great deal of what is known about remodeling dynamics. Compared with limb bones, ribs are metabolically more active and sensitive to hormonal changes, and receive frequent low-strain loading. Optimization for calcium exchange in rib osteons might be achieved without incurring a significant reduction in safety factor by disproportionally increasing central canal size with increased osteon size (positive allometry). By contrast, greater mechanical loads on limb bones might favor reducing deleterious consequences of intracortical porosity by decreasing osteon canal size with increased osteon size (negative allometry). Evidence of this metabolic/mechanical dichotomy between ribs and limb bones was sought by examining relationships between Haversian canal surface area (BS, osteon Haversian canal perimeter, HC.Pm) and bone volume (BV, osteonal wall area, B.Ar) in a broad size range of mature (quiescent) osteons from adult human limb bones and ribs (modern and medieval) and various adult and subadult non-human limb bones and ribs. Reduced major axis (RMA) and least-squares (LS) regressions of HC.Pm/B.Ar data show that rib and limb osteons cannot be distinguished by dimensional allometry of these parameters. Although four of the five rib groups showed positive allometry in terms of the RMA slopes, nearly 50% of the adult limb bone groups also showed positive allometry when negative allometry was expected. Consequently, our results fail to provide clear evidence that BS/BV scaling reflects a rib versus limb bone dichotomy whereby calcium exchange might be preferentially enhanced in rib osteons.

Link to Article

http://dx.doi.org/10.1002/ajpa.22270

Positive regulation of osteogenesis by bile acid through FXR

Authors

Sun Wook Cho MD, Jee Hyun An MD, Hyojung Park PhD, Jae-Yeon Yang MS, Hyung Jin Choi MD, Sang Wan Kim MD, Young Joo Park MD, Seong Yeon Kim MD, Mijung Yim PhD, Wook-Young Baek PhD, Jung-Eun Kim MD, Chan Soo Shin MD

Abstract

Farnesoid X receptor (FXR) is a nuclear receptor, which functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR−/−) in vivo resulted in a significant reduction in bone mineral density by 4.3∼6.6% in mice 8 to 20 weeks of age compared with FXR+/+ mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, TRACP staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR−/− mice compared with FXR+/+ mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR−/− mice compared with FXR+/+ mice in concert with a significant reduction in Col1a1, ALP, and Runx2 gene expressions. Cultures of bone marrow derived macrophages from FXR−/− mice exhibited an increased number of osteoclast formations and protein expression of NFATc1. In female FXR−/− mice, although BMD was not significantly different from that in FXR+/+ mice, bone loss was accelerated after an ovariectomy compared with FXR+/+ mice. In vitro, activation of FXR by bile acids (CDCA or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced ERK and β-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol diet (1%) marginally prevented OVX-induced bone loss and enhanced bone mass gain in growing C57BL/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways, i.e. bone formation and resorption.

Link to Article

http://dx.doi.org/10.1002/jbmr.1961

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Authors

Tao Yang, Ingo Grafe, Yangjin Bae, Shan Chen, Yuqing Chen, Terry K. Bertin, Ming-Ming Jiang, Catherine G. Ambrose, and Brendan Lee

Abstract

TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro–TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1−/− mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1−/− osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1−/− osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast–osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1−/− calvaria exhibit an elevated mature TGF-β/pro–TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan–TGF-β antibody, significantly improved the low bone mass of Esl-1−/− mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1−/− mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast–osteoclast coupling.

Link to Article

http://dx.doi.org/10.1073/pnas.1219748110

Increased Bone Mass in Mice Lacking the Adipokine Apelin

Authors

Lalita Wattanachanya, Wei-Dar Lu, Ramendra K. Kundu, Liping Wang, Marcia J. Abbott, Dylan O'Carroll, Thomas Quertermous and Robert A. Nissenson

Abstract

Adipose tissue plays an important role in skeletal homeostasis, and there is interest in identifying adipokines that influence bone mass. One such adipokine may be apelin, a ligand for the Gi-G protein-coupled receptor APJ, which has been reported to enhance mitogenesis and suppress apoptosis in MC3T3-E1 cells and primary human osteoblasts (OBs). However, it is unclear whether apelin plays a physiological role in regulating skeletal homeostasis in vivo. In this study, we compared the skeletal phenotypes of apelin knockout (APKO) and wild-type mice and investigated the direct effects of apelin on bone cells in vitro. The increased fractional cancellous bone volume at the distal femur was observed in APKO mice of both genders at 12 weeks of age and persisted until the age of 20. Cortical bone perimeter at the femoral midshaft was significantly increased in males and females at both time points. Dynamic histomorphometry revealed that APKO mice had increased rates of bone formation and mineral apposition, with evidences of accelerated OB proliferation and differentiation, without significant alteration in osteoclast activity. An in vitro study showed that apelin increased proliferation of primary mouse OBs as well as suppressed apoptosis in a dose-dependent manner with the maximum effect at 5nM. However, it had no effect on the formation of mineralized nodules. We did not observed significantly altered in osteoclast parameters in vitro. Taken together, the increased bone mass in mice lacking apelin suggested complex direct and paracrine/endocrine effects of apelin on bone, possibly via modulating insulin sensitivity. These results indicate that apelin functions as a physiologically significant antianabolic factor in bone in vivo.

Link to Article

http://dx.doi.org/10.1210/en.2012-2034

Immediately Placed Implants in Periodontally Compromised Patients: A Prospective Clinical Study

Authors

Rehab Elsharkawy and Hala El-Menoufy

Abstract

Purpose: This study was done to compare the outcome of implants placed immediately in partially edentulous periodontally compromised to periodontally healthy patients clinically and radiographically. Material and methods: Twenty immediately placed implants were followed up one year after loading clinically and radiographically. Patients were divided into 2 groups: 10 implants in group H (healthy, n=9) and 10 implants in group PD (moderate to severe chronic periodontitis, n=7). Clinical (modified bleeding index mBI, modified plaque index mPI, probing pocket depth PPD and degree of mobility using Periotest device) and radiographic parameters (Bone implant contact ratio BICR and vertical bone resorption) were assessed. Results: There were no significant differences in implant success rate between the 2 groups. Since the time of loading till the end of follow up period all implants were immobile, there was no pain or suppuration around the implants and there were no evidence of peri-implant radiolucency in the x-rays. Through all periods; there was no statistically significant difference between the two groups in the mPI or PPD, at any time point. At loading and 3 months post-loading; PD group showed statistically significantly higher mean mBI than healthy group. PD group showed statistically significantly lower mean PTVs (more stability) at time of loading (-1±2.1) and at 3 months PL (-1 ±1.8) than the H group at loading (0.5±0.7) and 3 ms PL (0.6±2) where P was 0.022 and 0.031for L and 3 ms PL respectively. Regarding the radiographic measures, there were no statistically significant differences between the two groups in the BICR and the VBL at any time point, through all the follow up periods P value ≤ 0.05. Conclusion: Immediate implants may be successful treatment modality in partially edentulous patients suffering from moderate to severe chronic periodontitis, provided that careful debridement of the extraction sockets is done and a good maintenance protocol is followed.

Link to Article

http://www.jofamericanscience.org/journals/am-sci/am0903/067_16822am0903_426_434.pdf

The Ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation

Authors

Koichiro Ono, Matthew R. Karolak, Jean de la Croix Ndong, Weixi Wang, Xiangli Yang and Florent Elefteriou

Abstract

The severe defects in growth plate development caused by chondrocyte extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) gain or loss-of-function suggest that tight spatial and temporal regulation of mitogen-activated protein kinase signaling is necessary to achieve harmonious growth plate elongation and structure. We provide here evidence that neurofibromin, via its Ras guanosine triphosphatase -activating activity, controls ERK1/2-dependent fibroblast growth factor receptor (FGFR) signaling in chondrocytes. We show first that neurofibromin is expressed in FGFR-positive prehypertrophic and hypertrophic chondrocytes during growth plate endochondral ossification. Using mice lacking neurofibromin 1 (Nf1) in type II collagen-expressing cells, (Nf1col2−/− mutant mice), we then show that lack of neurofibromin in post-mitotic chondrocytes triggers a number of phenotypes reminiscent of the ones observed in mice characterized by FGFR gain-of-function mutations. Those include dwarfism, constitutive ERK1/2 activation, strongly reduced Ihh expression and decreased chondrocyte proliferation and maturation, increased chondrocytic expression of Rankl, matrix metalloproteinase 9 (Mmp9) and Mmp13 and enhanced growth plate osteoclastogenesis, as well as increased sensitivity to caspase-9 mediated apoptosis. Using wildtype (WT) and Nf1−/− chondrocyte cultures in vitro, we show that FGF2 pulse-stimulation triggers rapid ERK1/2 phosphorylation in both genotypes, but that return to the basal level is delayed in Nf1−/− chondrocytes. Importantly, in vivo ERK1/2 inhibition by daily injection of a recombinant form of C-type natriuretic peptide to post-natal pups for 18 days was able to correct the short stature of Nf1col2−/− mice. Together, these results underscore the requirement of neurofibromin and ERK1/2 for normal endochondral bone formation and support the notion that neurofibromin, by restraining RAS-ERK1/2 signaling, is a negative regulator of FGFR signaling in differentiating chondrocytes.

Link to Article

http://dx.doi.org/10.1093/hmg/ddt162