Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca² pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases.

Surigical site infection has been a challenge for surgeons for many years, the prevalence of serum albumin <3.5g/dL has been reported to be associated with increased orthopaedic complications. However, the prognostic implications and significance of serum albumin <3.5g/dL after orthopaedic surgeries remain ambiguity. In this study, we performed a meta-analysis to access the predictive value of serum albumin level on SSI. A basic data search was performed in PubMed and Web of Science, in addition, references were manually searched. All of the observational studies contained preoperative albumin, outcomes of SSI or valuable data that could be abstracted and analysed for meta-analysis in orthopaedics. All of the studies were assessed using the classic Newcastle Ottawa Scale (NOS). They conformed to critical quality evaluation standards, and the final data analysis was performed with RevMan 5.2 software. A total of 112,183 patients included in 13 studies were involved. The pooled MD of albumin between the infection group and the non-infection group was MD = −2.28 (95 % CI −3.97–0.58), which was statistically significant (z = 2.63, P = 0.008). The pooled RR of infection when comparing albumin 3.5 was 2.39 (95 % CI 1.57 3.64), which was statistically significant (z = 4.06, P < 0.0001). Heterogeneity were found in the pooled MD of albumin and in the pooled RR for infection (P = 0.05, I2 = 61 % and P = 0.003, I2 = 68 %). No publication bias occurred based on two basically symmetrical funnel plots. Our meta-analysis demonstrated that an albumin level <3.5 g/dL had an almost 2.5 fold increased risk of SSI in orthopaedics, although this conclusion requires well-designed prospective cohort studies to be confirmed further.

Although many studies have reported risk factors of mortality following hip fracture surgery, the preventable risk factors of mortality following hip fracture surgery have not been well-identified. The aim of this study was to identify the preventable risk factors of mortality following hip fracture surgery. We searched PubMed, Web of Science, Google scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases from January 1997 to March 2017 for studies reporting risk factors of mortality following hip fracture surgery. The primary outcomes assessed in this meta-analysis were time to surgery, residential status, smoking, cardiovascular disease, pulmonary disease, diabetes, and malignancy. All analyses were conducted using Stata/SE version 11.0 software. Sixteen studies involving 25 349 patients meeting the inclusion criteria were included. Statistically significant associations between the mortality after hip fracture surgery and the risk factors, including the time to surgery (>2days/1day/2days/<2days), pulmonary disease, diabetes, and cardiovascular disease significantly increased the risk of mortality after hip fracture surgery. These preventable risk factors may be used to create algorithms that are more effective and pertinent to reduce the mortality following hip fracture surgery.

Many positive signalling pathways of osteoclastogenesis have been characterized, but negative signalling pathways are less well studied. Here we show by microarray and RNAi that guanine nucleotide-binding protein subunit α13 (Gα13) is a negative regulator of osteoclastogenesis. Osteoclast-lineage-specificGna13conditional knockout mice have a severe osteoporosis phenotype.Gna13-deficiency triggers a drastic increase in both osteoclast number and activity (hyper-activation), mechanistically through decreased RhoA activity and enhanced Akt/GSK3β/NFATc1 signalling. Consistently, Akt inhibition or RhoA activation rescues hyper-activation ofGna13-deficient osteoclasts, and RhoA inhibition mimics the osteoclast hyperactivation resulting fromGna13-deficiency. Notably, Gα13 gain-of-function inhibits Akt activation and osteoclastogenesis, and protects mice from pathological bone loss in disease models. Collectively, we reveal that Gα13 is a master endogenous negative switch for osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signalling pathway, and that manipulating Gα13 activity might be a therapeutic strategy for bone diseases.

Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1^f/fTwist2-Cre) and osteoblast-specific (Runx1^f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2^-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.