The contribution of inflammation to bone loss is well documented in arthritis and other diseases with an emphasis on how inflammatory cytokines promote osteoclastogenesis. Macrophages are the major producers of cytokines in inflammation, and the factors they produce depend upon their activation state or polarization. In recent years, it has become apparent that macrophages are also capable of interacting with osteoblasts and their mesenchymal precursors. This interaction provides growth and differentiation factors from one cell that act on the other and visa versa-a concept akin to the requirement for a feeder layer to grow hemopoietic cells or the coupling that occurs between osteoblasts and osteoclasts to maintain bone homeostasis. Alternatively, activated macrophages are the most likely candidates to promote bone formation and have also been implicated in the tissue repair process in other tissues. In bone, a number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo. This review discusses the different cell types involved, cellular mediators, and how this can be used to direct new bone anabolic approaches.

Macrophage Polarization and Bone Formation: A review.

5042 Oncostatin M (OSM), an IL-6 family cytokine, has previously been shown to inhibit the proliferation of several breast cancer cell lines in vitro. Our studies report additional effects of OSM treatment on the human breast carcinoma cell line T-47D. OSM treatment of T-47D cells for 1 to 3 days alters cell morphology from a normal epithelial phenotype to more mesenchymal phenotype. These changes are followed by a 250% increase in cell detachment after 5 to 8 days of OSM treatment. Detached aggregates of cells are viable and easily readhere to several extracellular matrix components. In addition, immunoblots of concentrated conditioned media collected from OSM-treated T-47D cells showed an increase in the expression of the proteases cathepsin D and cathepsin L, which have been implicated in metastasis. Importantly, OSM treated T-47D cells show an almost 300% increase in invasive capacity as measured by the Matrigel invasion chamber assay. Collectively, these data demonstrate that OSM induces a metastatic phenotype in T-47D cells in vitro, and suggest that OSM could enhance metastasis in vivo. Our results suggest that experimental therapeutic approaches utilizing OSM as a treatment for human breast cancer should proceed with caution, and that OSM itself may be a valid therapeutic target.

Oncostatin M induces detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

/pdf/a-role-for-soluble-il-6-receptor-in-osteoarthritis-4qzxug80be.pdf

A Role for Soluble IL-6 Receptor in Osteoarthritis

The ideal implant for the treatment of an unstable intertrochanteric femoral fracture is still a matter of discussion. The aim of this systematic review is to conduct a network meta-analysis of randomized controlled trials (RCTs) comparing clinical outcomes between dynamic hip screws (DHS), Medoff sliding plating, percutaneous compression plating (PCCP), proximal femoral nails (PFN), Gamma nails and less invasive stabilization system fixation in femoral trochanteric fractures in the elderly. These clinical outcomes consist of total intra-operative time, intra-operative fluoroscopy time, intra-operative blood loss, blood component transfusion, length of hospital stay, postoperative general complications, wound complications, late complications and reoperation rates. This systematic review was conducted using PubMed and Scopus search engines for RCTs comparing clinical outcomes between treatments from inception to February 22, 2015. Thirty-six of 785 studies identified were eligible. Compared to the other implants, PCCP showed the lowest total operative time and units of blood transfusion with an unstandardized mean difference (UMD) of 29.27 min (95% CI 5.24, 53.50) and 0.89 units (95% CI 0.52, 1.25). The lowest incidence of general complications, wound complications and late complications of PCCP was 0.09 (95% CI 0.04, 0.18), 0.01 (95% CI 0.01, 0.04) and 0.05 (95% CI 0.02, 0.11), respectively, when compared to others. The lowest fluoroscopic time was with DHS with an UMD of 0.24 min (95% CI 0.16, 0.32), whereas the lowest blood loss and shortest hospital stay were with PFN with an UMD of 233.61 ml of blood loss (95% CI 153.17, 314.04) and 7.23 days of hospital stay (95% CI 7.15, 7.31) when compared to all other fixation methods. Reoperation rates of all implants had no statistically significant difference. The network meta-analysis suggested that fixation with PCCP significantly shortens operative time and decreases the units of blood transfusion required, while also lowering risks of general complications, wound complications and late complications when compared to fixation. Use of PFN showed the least intra-operative blood loss and shortest hospital stay. Multiple active treatment comparisons indicate that PCCP fixation in trochanteric fractures in the elderly is the treatment of choice in terms of intra-operative outcomes and postoperative complications.

Comparative outcome of PFNA, Gamma nails, PCCP, Medoff plate, LISS and dynamic hip screws for fixation in elderly trochanteric fractures: a systematic review and network meta-analysis of randomized controlled trials

The choice between intramedullary (IM) nailing or plating of distal tibia fractures without articular involvement remains controversial. A meta-analysis of randomized controlled trials (RCTs) and observational studies was performed to compare IM nailing with plating for distal tibia fractures without articular involvement and to determine the dominant strategy. The PubMed, Embase, Cochrane Library databases, Chinese Wan-Fang Database, and China National Knowledge Infrastructure were searched. Twenty-eight studies, which included 1863 fractures, met the eligible criteria. The meta-analysis did not identify a statistically significant difference between the two treatments in terms of the rate of deep infection, delayed union, removal of instrumentation, or secondary procedures either in the RCT or retrospective subgroups. IM nailing was associated with significantly more malunion events and a higher incidence of knee pain in the retrospective subgroup and across all the studies, but not significantly in the RCT subgroup, and a lower rate of delayed wound healing and superficial infection both in the RCT and retrospective subgroups relative to plating. A meta-analysis of the functional scores or questionnaires was not possible because of the considerable variation among the included studies, and no significant differences were observed. Evidence suggests that both IM nailing and plating are appropriate treatments as IM nailing shows lower rate of delayed wound healing and superficial infection and plating may avoid malunion and knee pain. These findings should be interpreted with caution, however, because of the heterogeneity of the study designs. Large, rigorous RCTs are required.

/pdf/intramedullary-nailing-versus-plating-for-distal-tibia-yrh14a6i6f.pdf

Intramedullary nailing versus plating for distal tibia fractures without articular involvement: a meta-analysis

Knee osteoarthritis (OA) is the most prevalent type of OA and the cytokine, oncostatin M (OSM), may contribute to the pathogenesis of OA. However, the exact role of OSM in the development of knee OA and the underlying mechanisms are not yet fully understood. This study was designed to detect the expression of OSM in the synovial tissue of patients with knee OA. Furthermore, we investigated whether Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation. The synovial tissue of the knee joint was collected from 32 patients with knee OA. We detected OSM mRNA and protein expression (by RT-qPCR and western blot analysis, respectively) in the synovial tissue of the knee joint, and the expression level of OSM was higher in the patients with knee OA compared with the controls. MTT assay was used in the in vitro experiments to determine MC3T3-E1 cell proliferation, and cell differentiation was determined by measuring alkaline phosphatase (ALP) activity and osteocalcin (OCN) expression. The results from our in vitro experiments revealed that OSM induced bone formation by increasing osteoblast cell proliferation and differentiation. In addition, the expression levels of Notch ligand, receptor and target gene, including Delta-like 1 (Dll1), Notch homolog 1 (Notch1) and Hes family bHLH transcription factor 1 (Hes1) were decreased following treatment with OSM in a time-dependent manner in the MC3T3-E1 cells. A Dll1 overexpression vector was transfected into the cells to activate Notch signaling, and the results revealed that the activation of Notch signaling attenuated the effects of OSM on MC3T3-E1 cell proliferation and differentiation. In conclusion, our data demonstrate that elevated levels of OSM in synovial tissue induce bone formation by increasing osteoblast cell proliferation and differentiation. The Notch signaling pathway was found to be one of the signaling pathways that inhibit OSM-induced MC3T3-E1 cell proliferation and differentiation. The findings of this study may broaden our understanding of the mechanisms behing the role of OSM in the development of knee OA.

/pdf/osm-is-overexpressed-in-knee-osteoarthritis-and-notch-29th9lss6r.pdf

OSM is overexpressed in knee osteoarthritis and Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation

Objective
To compare the efficacies of minimally invasive plate osteosynthesis (MIPPO) and interlocking intramedullary nailing (IMN) in the treatment of extra-articular fractures of distal tibia.


Methods
Retrospective reviews were conducted for 126 patients with extra-articular distal tibia fractures.Treatment was either MIPPO (n=61) or IMN (n=65).The outcomes were assessed by comparing operating duration, time to union, the last follow-up American Orthopedic Foot and Ankle Society (AOFAS) score and complication rate.


Results
The average follow-up period was 23.7 (12-53) months.In the minimally invasive plate osteosynthesis group, there were deep infections (n=2), superficial infections (n=5), delayed union (n=2), malunion (n=2) and knee joint pain (n=10) were observed.In addition, the average operating duration (85.9±18.9 min), average time to union (17.3±3.8 weeks) and average AOFAS (83.2±11.9) were analyzed.In the interlocking intramedullary nailing group, there were delayed union (n=3), malunion (n=12) and knee joint pain (n=22).And the average operating duration (83.3±15.7 min), average time to union (16.5±3.1 weeks) and average AOFAS (84.9±12.0) were analyzed.No statistical significance existed in operating duration, time to union and the last follow-up AOFAS between two groups (P>0.05).However, the rates of malformation and knee joint pain were higher in the intramedullary nail group than those in the plate group.And the difference was statistically significant (P=0.015, P=0.025).


Conclusion
Both MIPPO and IMN are effective for extra-articular fractures of distal tibia.However, the former has the advantage of lowers rate of malformation and knee joint pain.Therefore a surgeon should consider the degree of injury while managing extra-articular fracture of distal tibia.


Key words: 
Surgicalprocedures,minimallyinvasive; Fracturefixation,internal; Tibialfractures; Bonenails

[Locked plating with minimally invasive percutaneous plate osteosynthesis versus intramedullary nailing of distal extra-articular tibial fracture: a retrospective study].

Objective
To assess the efficacies of proximal femoral nail antirotation (PFNA) versus dynamic hip screw (DHS) for intertrochanteric fracture in elders.


Methods
The databases of PubMed, Embase, CENTRAL, CBM, CNKI and WANFANG were searched for the relevant randomized controlled trials (RCTs) up to May 18, 2013. After quality evaluation and data extraction by two authors independently, meta-analyses were performed with the RevMan5.1 software. And the levels of evidence were evaluated by the GRADEprofile 3.6 software.


Results
A total of 17 studies (n=1 344) were included and there were 656 patients in PFNA group and 688 in DHS respectively. Meta-analyses showed that, as compared with DHS, PFNA could significantly decrease fixation failure rate (odds ratio (OR)=0.26, 95% confidence interval (CI)=[0.12,0.57], P=0.0008), reduce average fracture healing time (weighted mean difference (WMD)=-15.11, 95%CI=[-24.36,-5.85], P=0.001), improve excellent and good rate for Harris score (OR=0.29, 95%CI=[0.15,0.56], P=0.0002), yield a higher Harris score (WMD=6.88, 95%CI=[0.96,12.80], P=0.02) and reduce the rate of coxa vara (OR=0.40, 95%CI=[0.18,0.92], P=0.03). However, there was no statistical significance in 1-year mortality, postoperative nonunion and delayed union, postoperative femoral head necrosis, postoperative femoral fractures or femoral head necrosis. The importance of outcomes was "critical". And the level of evidences based on the GRADE approach was from "very low" to "low".


Conclusion
PFNA is superior to DHS. Due to the limitations of the included studies, more large-sample and high-quality RCTs are required. And subgroup analysis based on fracture types should be performed.


Key words: 
Femural fractures; Fractures fixation, internal; Bone nail; Meta-analysis

Libin Peng

Papers

OSM is overexpressed in knee osteoarthritis and Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation

[Locked plating with minimally invasive percutaneous plate osteosynthesis versus intramedullary nailing of distal extra-articular tibial fracture: a retrospective study].

[Proximal femoral nail antirotation versus dynamic hip screw for intertrochanteric fracture in elders: a meta-analysis].