Adipose-derived stem cells (ASCs) and mesenchymal stem cells are promising for tissue repair because of their multilineage differentiation capacity. Our previous data confirmed that the implantation of mixed ASCs and chondrocytes into cartilage defects induced desirable in vivo healing outcomes. However, the paracrine action of ASCs on chondrocytes needs to be further elucidated. In this study, we established a co-culture system to achieve cell-to-cell and cell-to-tissue crosstalk and explored the soluble growth factors in both ASCs and chondrocytes supplemented with 1% fetal bovine serum to mimic the physiological microenvironment. In ASCs, we screened for growth factors by semi-quantitative PCR and quantitative real-time PCR and found that the expression of bone morphogenetic protein 2 (BMP-2), vascular endothelial growth factor B (VEGFB), hypoxia inducible factor-1α (HIF-1α), fibroblast growth factor-2 (FGF-2), and transforming growth factor-β1 significantly increased after co-culture in comparison with mono-culture. In chondrocytes, VEGFA was significantly enhanced after co-culture. Unexpectedly, the expression of collagen II and aggrecan was significantly down-regulated in the co-culture group compared with the mono-culture group. Meanwhile, among all the growth factors screened, we found that the BMP family members BMP-2, BMP-4, and BMP-5 were down-regulated and that VEGFB, HIF-1α, FGF-2, and PDGF were significantly decreased after co-culture. These results suggest that crosstalk between ASCs and chondrocytes is a pathway through the regulated growth factors that might have potential in cartilage repair and regeneration and could be useful for tissue engineering.

Cartilage repair: Cell cross-talk potential key to tissue engineering

Cartilage cells and stem cells from fat tissue affect each other in ways that could be harnessed to improve cartilage repair. Yunfeng Lin and colleagues from Sichuan University, Chengdu, China, previously showed that implantation of adipose-derived stem cells and cartilage cells into rabbit knee promoted good cartilage repair. In this study, they aimed to reveal the mechanisms involved. The researchers cultured both cell types (from rats) alone and together to see how they affected each other. Co-culture altered the expression of several genes related to growth and proliferation in both cell types, and the growth and structures of the cells were changed. The researchers conclude that cross-talk between the cell types alters their properties and affects their ability to generate cartilage cells. Manipulation of the mechanism could improve tissue engineering for cartilage repair.

Histomorphometric analysis of histologic sections of normal and diseased bone samples, such as healing allografts and fractures, is widely used in bone research. However, the utility of traditional semi-automated methods is limited because they are labor-intensive and can have high interobserver variability depending upon the parameters being assessed, and primary data cannot be re-analyzed automatically. Automated histomorphometry has long been recognized as a solution for these issues, and recently has become more feasible with the development of digital whole slide imaging and computerized image analysis systems that can interact with digital slides. Here, we describe the development and validation of an automated application (algorithm) using Visiopharm’s image analysis system to quantify newly formed bone, cartilage, and fibrous tissue in healing murine femoral allografts in high-quality digital images of H&E/alcian blue-stained decalcified histologic sections. To validate this algorithm, we compared the results obtained independently using OsteoMeasure^TM and Visiopharm image analysis systems. The intraclass correlation coefficient between Visiopharm and OsteoMeasure was very close to one for all tissue elements tested, indicating nearly perfect reproducibility across methods. This new algorithm represents an accurate and labor-efficient method to quantify bone, cartilage, and fibrous tissue in healing mouse allografts.

Bone repair: tissue analysis automated

The analysis of bone architecture has been made faster and more reliable by the development of a fully automated system. The process has been semi-automated for over 30 years, but identifying and quantifying different tissue types has remained time-consuming and susceptible to errors. Brendan Boyce and colleagues at the University of Rochester Medical Center, USA, have developed a system that automates much more of the process. They combined the digitization of microscope images with image analysis software that could identify different tissue types according to their colours when stained. The system reduced the time required for analysis, and reliably distinguished between new bone, cartilage and fibrous tissue using two different image analysis systems. The automated system could help with monitoring bone healing after bone grafts and fractures.

Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.

Osteoarthritis: Treatments for mobility

Next-generation therapies for osteoarthritis strive to go beyond symptom relief to achieve actual repair of damaged joint tissue. Existing treatments do little more than ease the pain for many elderly patients experiencing the painful cartilage degradation and bone growth associated with this disease. University of Western Australia researcher Jiake Xu and colleagues have reviewed a variety of treatments that are currently in the clinical pipeline which might offer a more meaningful restoration of joint function. Some are OA drugs that slow disease progression and tissue damage, while others promise to repair OA-related injuries. These include treatments based on biologic agents and regenerative therapies that could promote natural regeneration of cartilage at the joint. Finally, the authors examine a handful of potential therapies that are showing preclinical promise in animal models.

Mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 were created and characterized. Mice lacking either gene alone were viable and fertile with normal knee morphology. Mice in which both Lrp5 and Lrp6 were conditionally ablated via Collagen2a1-cre-mediated deletion displayed severe defects in skeletal development during embryogenesis. In addition, adult mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 displayed low bone mass suggesting that the Collagen2a1-cre transgene was active in cells that subsequently differentiated into osteoblasts. In both embryonic skeletal development and establishment of adult bone mass, Lrp5 and Lrp6 carry out redundant functions.

Embryonic development: Sorting out a pair of bone builders

Two proteins play overlapping and essential roles in the formation of the skeleton during embryonic development. Low-density lipoprotein-related receptors, Lrp5 and Lrp6, respond to signals responsible for bone development. Mice completely lacking either receptor protein exhibit serious or lethal developmental defects. Researchers led by Bart Williams of the Van Andel Research Institute in the USA have used a more focused approach to study Lrp5 and Lrp 6, using genetically modified mice in which these proteins are only absent from cartilage- and bone-forming cell types. The loss of both proteins is catastrophic, with mice perishing before birth with severe skeletal abnormalities. Mice with localized loss of either Lrp5 or Lrp6 survive to adulthood, albeit with reduced bone mass, indicating that these proteins essentially act redundantly to facilitate bone development in these cell types.

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score (TBS) and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT (HRpQCT) imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct (AGE) accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting ¹⁸F-fluorodeoxyglucose ([¹⁸F]-FDG) and non-invasive, high-resolution positron emission tomography/computed tomography (PET/CT) imaging and ex vivo autoradiography. Assessment of [¹⁸F]-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog. Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that [¹⁸F]-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of [¹⁸F]-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism.

Metabolism: Glucose uptake and distribution in bones

The skeleton is a site of significant glucose uptake, which is regulated by insulin and affected by whole body metabolic changes. According to Ryan Riddle and DanielThorek from the Johns Hopkins University School of Medicine, Baltimore, US, and colleagues, little is known about the energy requirements of bone cells,despite evidence linking bone growth to energy intake. Using radiolabelled glucose analogs in mice, they found evidence of glucose uptake within the bone cells, particularly within spongy bone. The extent of glucose uptake exceeded that of other glucose-storing organs such as the liver and muscle. The uptake appeared to be regulated by insulin. The findings suggest that the skeleton should be considered as a possible site of significant glucose disposal and a major component of whole body glucose metabolism.

Bone morphogenetic proteins (BMPs) have multiple roles in skeletal development, homeostasis and regeneration. BMPs signal via type I and type II serine/threonine kinase receptors (BMPRI and BMPRII). In recent decades, genetic studies in humans and mice have demonstrated that perturbations in BMP signaling via BMPRI resulted in various diseases in bone, cartilage, and muscles. In this review, we focus on all three types of BMPRI, which consist of activin-like kinase 2 (ALK2, also called type IA activin receptor), activin-like kinase 3 (ALK3, also called BMPRIA), and activin-like kinase 6 (ALK6, also called BMPRIB). The research areas covered include the current progress regarding the roles of these receptors during myogenesis, chondrogenesis, and osteogenesis. Understanding the physiological and pathological functions of these receptors at the cellular and molecular levels will advance drug development and tissue regeneration for treating musculoskeletal diseases and bone defects in the future.

Molecular biology: Signaling receptors tied to bone disease

Understanding how a group of receptors activate growth factors called bone morphogenetic proteins (BMPs) could lead to new drug targets. BMPs are essential for proper development, and diseases of the bone, cartilage, and muscles have all been linked to aberrant BMP signaling. In a review article, a team led by Xinquan Jiang from Shanghai Jiao Tong University in China and Jian Feng from Texas A&M Baylor College of Dentistry in the USA discuss the essential roles of cell-surface BMP “type I” receptors in bone formation. Animal models have revealed the molecular ways in which all three kinds of type I receptors have distinct biological functions in a variety of cells. The authors note that modulating BMP signaling through these receptors could one day help patients with bone and muscle defects.

Correction to: Bone Research (2015) 3, 15032. doi:10.1038/boneres.2015.32 Since the online publication of the above article, it was noticed that the symbol indicating the statistical significance was missed in Figure 4a. The correct figure is shown here. The corrected article appears online togetherwith this corrigendum.

Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic skeletal development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during skeletal development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin–proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines’ signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, skeletal development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.

Deciphering bone-building signals

Two families of signaling proteins represent valuable targets for human diseases associated with defects in bone and cartilage development. Yi-Ping Li and colleagues at the University of Alabama at Birmingham have reviewed how pathways activated by transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) help coordinate the development and maintenance of the skeletal system. TGF-β and BMP can promote both the construction and disassembly of bone and cartilage, and modulate the behavior of cells that form these tissues. The outcomes resulting from pathway activation are shaped by interactions between further signaling proteins and other cellular pathways, and diverse other regulatory mechanisms. Treatments targeting these activated pathways have already shown promise for repairing fractures and other bone damage, and evidence suggests that patients with osteoarthritis and other skeletal disorders may benefit from similar approaches.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1α (HIF-1α) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1α mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1α and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1α protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1α expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1α inhibitors decreased HIF-1α and FGF23 protein accumulation and inhibited HIF-1α-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1α consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1α inhibitor. These results show for the first time that HIF-1α is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1α activity in TIO contributes to the aberrant FGF23 production in these patients.

Insight into mechanism of tumor-related bone disease

Diagnosis and treatment of a rare tumor-induced bone disease could be improved by new insight into its pathogenesis. Thomas Clemens from Johns Hopkins School of Medicine and colleagues studied the molecular mechanisms that cause non-malignant tumors to release high levels of fibroblast growth factor 23 (FGF23), which in turn cause tumor-induced osteomalacia (TIO), a softening of bones due to excessive phosphate excretion. They focused on the role of the HIF-1α protein, a gene regulator that is involved in similar FGF23-dependent phosphate wasting diseases. In cells from the tumors of patients with TIO, HIF-1α expression was higher than normal, and its binding to DNA switched on expression of FGF23. The researchers concluded that HIF-1α directly regulates the expression of FGF23 in tumors, suggesting new opportunities for the development of diagnostic tests and treatment for TIO.

Growth differentiation factor 11 (GDF11) is an important circulating factor that regulates aging. However, the role of GDF11 in bone metabolism remains unclear. The present study was undertaken to investigate the relationship between serum GDF11 level, bone mass, and bone turnover markers in postmenopausal Chinese women. Serum GDF11 level, bone turnover biochemical markers, and bone mineral density (BMD) were determined in 169 postmenopausal Chinese women (47–78 years old). GDF11 serum levels increased with aging. There were negative correlations between GDF11 and BMD at the various skeletal sites. After adjusting for age and body mass index (BMI), the correlations remained statistically significant. In the multiple linear stepwise regression analysis, age or years since menopause, BMI, GDF11, and estradiol were independent predictors of BMD. A significant negative correlation between GDF11 and bone alkaline phosphatase (BAP) was identified and remained significant after adjusting for age and BMI. No significant correlation was noted between cross-linked N-telopeptides of type I collagen (NTX) and GDF11. In conclusion, GDF11 is an independent negative predictor of BMD and correlates with a biomarker of bone formation, BAP, in postmenopausal Chinese women. GDF11 potentially exerts a negative effect on bone mass by regulating bone formation.

Osteoporosis: A biomarker for age-dependent bone loss

A study in Chinese women reveals that levels of a protein circulating in the blood correlate with age-dependent bone loss. Although there is compelling evidence suggesting that growth differentiation factor 11 (GDF11) levels increase with age, different groups have obtained contradictory findings on its role in osteoporosis. Researchers led by GuangWei Wang at the Hunan University of Medicine and TieJian Jiang at the Xiangya Hospital of Central South University have now obtained evidence that this protein is linked with skeletal degeneration. After analyzing blood samples from 169 postmenopausal women, the researchers determined that elevated GDF11 levels correlated with reduced hip bone density and lower levels of an established protein biomarker of new bone formation. These findings offer additional support for GDF11 involvement in osteoporosis progression, although further research will be needed to clarify the mechanism.

In a world where increasing joint arthroplasties are being performed on increasingly younger patients, osteolysis as the leading cause of failure after total joint arthroplasty (TJA) has gained considerable attention. Ultra-high molecular weight polyethylene wear-induced osteolysis is the process by which prosthetic debris mechanically released from the surface of prosthetic joints induces an immune response that favors bone catabolism, resulting in loosening of prostheses with eventual failure or fracture. The immune response initiated is innate in that it is nonspecific and self-propagating, with monocytic cells and osteoclasts being the main effectors. To date, detecting disease early enough to implement effective intervention without unwanted systemic side effects has been a major barrier. These barriers can be overcome using newer in vivo imaging techniques and modules linked with fluorescence and/or chemotherapies. We discuss the pathogenesis of osteolysis, and provide discussion of the challenges with imaging and therapeutics. We describe a positron emission tomography imaging cinnamoyl-Phe-(D)-Leu-Phe-(D)-Leu-Phe-Lys module, specific to macrophages, which holds promise in early detection of disease and localization of treatment. Further research and increased collaboration among therapeutic and three-dimensional imaging researchers are essential in realizing a solution to clinical osteolysis in TJA.

Joint replacement: Imaging and early intervention may help manage complications

New imaging techniques could help people who undergo joint surgery avoid “wear debris” that can destroy the bone. In a review article, Quanjun Cui and colleagues from the University of Virginia, Charlottesville, USA, describe how the plastic from prosthetic joints can sometimes break down and accumulate in surrounding tissues. There, the material causes local inflammation that degrades the bone and loosens the prosthesis. The researchers discuss an innovative imaging method for detecting immune molecules that could help doctors detect early signs of bone damage, allowing them to select therapies that target the unwanted inflammation without serious side effects. The authors advocate this kind of imaging to manage complications arising from joint replacement operations, a problem that is likely to become more common with increasing numbers of joint surgeries being performed on younger patients.

The purpose of this study was to compare the functional outcomes, psychological impact, and complication rates associated with external fixation and volar or dorsal plating in relation to the functional parameters following treatment of intra-articular fractures of the distal radius (IFDR) in patients older than 65 years. We hypothesized that using volar or dorsal plating would improve functional outcomes, but that it would be associated with more complications and equivalent functional outcomes when compared with the external fixation group. A total of 123 consecutive patients suffering from IFDR were recruited into the study. The patients were measured for clinical, radiological, and psychosocial functioning outcomes and were followed up after 1 week and 3, 6 and 12 months. After 3 months, the plating group had better pronation (P=0.001), supination, (P=0.047) and extension (P=0.043) scores. These differences were somewhat attenuated by 6 months and disappeared at 1 year. The plating group had a greater occurrence of wound infection (P=0.043), tendonitis, (P=0.024) and additional surgery compared with the external fixation group. The only TNO-AZL Adult Quality of Life scores in the plating group that were lower than those in the external fixation group were in the “gross motor” category (walking upstairs, bending over, walking 500 yards; P=0.023). Internal fixation was more advantageous than external fixation in the early rehabilitation period; after 1 year the outcomes were similar. The plating group showed significantly higher levels of wound infection and tendonitis and had a greater need for additional surgeries.

Wrist fractures: To plate or not to plate?

Internal plating of wrist fractures in elderly patients results in more complications and no long-term benefit compared to external fixation. Wrist fractures involving the radius, a lower arm bone, are common, yet there has been little research on the best surgical treatment for elderly patients. To investigate, Li Cao and AihemaitijiangYusufu at The First Affiliated Hospital of Xinjiang Medical University in Urumqi, China, and colleagues randomized 123 wrist fracture patients to be treated with external fixation or internal plating and followed them up one week, 3, 6 and 12 months later. At 3 months, patients treated with plating had a better range of movement compared to the external fixation group, although these differences had reduced at 6 months and disappeared at 12 months. However, they experienced higher rates of wound infection, tendonitis and further surgery.

Hereditary vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disorder characterized by severe rickets, hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated alkaline phosphatase. This disorder is caused by homogeneous or heterogeneous mutations affecting the function of the vitamin D receptor (VDR), which lead to complete or partial target organ resistance to the action of 1,25-dihydroxy vitamin D. A non-consanguineous family of Chinese Han origin with one affected individual demonstrating HVDRR was recruited, with the proband evaluated clinically, biochemically and radiographically. To identify the presence of mutations in the VDR gene, all the exons and exon–intron junctions of the VDR gene from all family members were amplified using PCR and sequenced. The proband showed rickets, progressive alopecia, hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated alkaline phosphatase. She also suffered from epilepsy, which is rarely seen in patients with HVDRR. Direct sequencing analysis revealed a homozygous missense mutation c.122G>A (p.C41Y) in the VDR gene of the proband, which is located in the first zinc finger of the DNA-binding domain. Both parents had a normal phenotype and were found to be heterozygous for this mutation. We report a Chinese Han family with one individual affected with HVDRR. A homozygous missense mutation c.122G>A (p.C41Y) in the VDR gene was found to be responsible for the patient’s syndrome. In contrast to the results of treatment of HVDRR in other patients, our patient responded well to a supplement of oral calcium and a low dose of calcitriol.

Hereditary diseases: Vitamin D and bone formation

Hereditary vitamin D-resistant rickets (HVDRR) has been diagnosed in a patient with weak bone formation, near-total hair loss, and epilepsy. Although 45 different causative mutations have been identified globally, this is only the second case reported in a patient of Han Chinese descent. HVDRR is a rare hereditary disorder caused by mutation of the vitamin D receptor gene (VDR); patients’ cells cannot respond to vitamin D, which is essential for incorporating calcium into healthy bones. Weibo Xia at the Peking Union Medical College Hospital and colleagues in China identified a mutation in the DNA-binding region of VDR responsible for the patient’s symptoms. Remarkably, the patient’s condition improved following low doses of oral vitamin D and calcium. The authors hypothesize that this response is estrogen-dependent, and that this treatment may help other female adolescents with HVDRR.

We report here a method for the use of poly-l-lysine (PLL) to markedly improve the adenoviral transduction efficiency of primary murine osteoblasts and bone marrow stromal cells (BMSCs) in culture and in situ, which are typically difficult to transduce. We show by fluorescence microscopy and flow cytometry that the addition of PLL to the viral-containing medium significantly increases the number of green fluorescence protein (GFP)-positive osteoblasts and BMSCs transduced with an enhanced GFP-expressing adenovirus. We also demonstrate that PLL can greatly enhance the adenoviral transduction of osteoblasts and osteocytes in situ in ex vivo tibia and calvaria, as well as in long bone fragments. In addition, we validate that PLL can improve routine adenoviral transduction studies by permitting the use of low multiplicities of infection to obtain the desired biologic effect. Ultimately, the use of PLL to facilitate adenoviral gene transfer in osteogenic cells can provide a cost-effective means of performing efficient gene transfer studies in the context of bone research.

Genetics: Improved gene delivery boosts bone research

Gene delivery to bone cells has been improved by use of a common compound, potentially making bone research cheaper and more efficient. Delivery of genes to cultured bone and bone marrow cells can be used to study the effects of specific genes in bone development and disease, but the standard technique of delivering genes using adenovirus is inefficient. Joseph Stains from the University of Maryland School of Medicine and colleagues have shown that the technique can be improved by adding poly-L-lysine with the adenovirus. Poly-L-lysine increased the percentage of cells that genes were delivered to, and increased the efficiency of delivery to each cell. The technique provides a simple way to increase the efficiency of genetic experiments in bone cells and consequently reduce their cost.

Age-related osteoporosis is associated with the reduced capacity of bone marrow mesenchymal stem cells (BMSCs) to differentiate into osteoblasts instead of adipocytes. However, the molecular mechanisms that decide the fate of BMSCs remain unclear. In our study, microRNA-23a, and microRNA-23b (miR-23a/b) were found to be markedly downregulated in BMSCs of aged mice and humans. The overexpression of miR-23a/b in BMSCs promoted osteogenic differentiation, whereas the inhibition of miR-23a/b increased adipogenic differentiation. Transmembrane protein 64 (Tmem64), which has expression levels inversely related to those of miR-23a/b in aged and young mice, was identified as a major target of miR-23a/b during BMSC differentiation. In conclusion, our study suggests that miR-23a/b has a critical role in the regulation of mesenchymal lineage differentiation through the suppression of Tmem64.

Osteoporosis: Finding an age-related switch

Development of osteoporosis is linked to age-related decline in levels of two RNA molecules. Stem cells in the bone marrow (BMSCs) can turn into bone-generating cells (osteoblasts) or fat cells (adipocytes). In older individuals, the transition to adipocytes is more likely, leading to fatty bone marrow, bone loss, and osteoporosis. The molecular mechanisms underlying this age-related shift remained unclear. Zhangyuan Lin at the Xiangya Hospital of Central South University, China, and co-workers have identified two short, non-coding microRNAs, miR-23a and b, that regulate this shift. They found that bone marrow samples from young mice and humans contained higher levels of these microRNAs than those from older individuals. Using cultured mouse BMSCs, they confirmed that increasing or decreasing miR-23a and b correspondingly increased or decreased osteoblast formation. These results may facilitate development of novel therapies for osteoporosis.

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 ^+/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 ^+/− mice and wild-type controls (Lrp6 ^+/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 ^+/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

Genetics: Mutation linked to impaired fracture healing

A gene defect linked to changes in bone mass in humans also impairs fracture healing in mouse models. The Wnt signaling pathway has emerged as a central regulator of skeletal remodeling, and some studies have found that people with mutations in one Wnt-associated gene called LRP6 have decreased bone mineral density and more fractures resulting from normal activities. To investigate the role of LRP6 in fracture healing, a team led by Bart Williams from the Van Andel Research Institute in Grand Rapids, Michigan, USA, bred mice with only one working copy of the gene. (Mice with two defective copies die before birth.) They induced fractures in the leg bone and four weeks later observed that the mutant mice had decreased density and volume in the healing bone, with fewer signs of tissue repair than normal mice.

Infection is one of the major causes of failure of orthopedic implants. Our previous study demonstrated that nanotube modification of the implant surface, together with nanotubes loaded with quaternized chitosan (hydroxypropyltrimethyl ammonium chloride chitosan, HACC), could effectively inhibit bacterial adherence and biofilm formation in vitro. Therefore, the aim of this study was to further investigate the in vitro cytocompatibility with osteogenic cells and the in vivo anti-infection activity of titanium implants with HACC-loaded nanotubes (NT-H). The titanium implant (Ti), nanotubes without polymer loading (NT), and nanotubes loaded with chitosan (NT-C) were fabricated and served as controls. Firstly, we evaluated the cytocompatibility of these specimens with human bone marrow-derived mesenchymal stem cells in vitro. The observation of cell attachment, proliferation, spreading, and viability in vitro showed that NT-H has improved osteogenic activity compared with Ti and NT-C. A prophylaxis rat model with implantation in the femoral medullary cavity and inoculation with methicillin-resistant Staphylococcus aureus was established and evaluated by radiographical, microbiological, and histopathological assessments. Our in vivo study demonstrated that NT-H coatings exhibited significant anti-infection capability compared with the Ti and NT-C groups. In conclusion, HACC-loaded nanotubes fabricated on a titanium substrate show good compatibility with osteogenic cells and enhanced anti-infection ability in vivo, providing a good foundation for clinical application to combat orthopedic implant-associated infections.

Bone implants: Staving off infection

A new weapon using ultrasmall tubes loaded with a broad spectrum antibacterial agent is now available against implant-associated infections. Metal rods inserted into the bone cavity speed up recovery from tibia and femur bone fractures. However, bacterial adhesion and buildup on implant surfaces may induce infection, especially in the treatment of open fractures, causing implant failure. To prevent infection, Tingting Tang and coworkers from Shanghai Jiao Tong University, China, have developed titanium nanotube arrays loaded with the antimicrobial agent quaternarized chitosan. They generated the nanotubes by electrochemically modifying the implant surface before adding the chitosan derivative. The arrays promoted bone cell attachment, proliferation, and growth to a greater extent than unmodified titanium in human cells. Moreover, they exhibited enhanced anti-infection activity when implanted in rat models inoculated with methicillin-resistant Staphylococcus aureus bacteria.

Although cartilage degradation is the characteristic feature of osteoarthritis (OA), it is now recognized that the whole joint is involved in the progression of OA. In particular, the interaction (crosstalk) between cartilage and subchondral bone is thought to be a central feature of this process. The interface between articular cartilage and bone of articulating long bones is a unique zone, which comprises articular cartilage, below which is the calcified cartilage sitting on and intercalated into the subchondral bone plate. Below the subchondral plate is the trabecular bone at the end of the respective long bones. In OA, there are well-described progressive destructive changes in the articular cartilage, which parallel characteristic changes in the underlying bone. This review examines the evidence that biochemical and biomechanical signaling between these tissue compartments is important in OA disease progression and asks whether such signaling might provide possibilities for therapeutic intervention to halt or slow disease development.

Osteoarthritis: Communication between cartilage and bone

Communications between cartilage and underlying bone could play a vital role in the progression of osteoarthritis (OA). During OA, a condition characterized by joint pain and swelling, cell behavior and molecular expression in bone and cartilage are altered, but exactly how the two tissues interact and respond to such changes is unclear. David Findlay and Julia Kuliwaba from the University of Adelaide, Australia, reviewed current understanding of cartilage-bone interplay in both healthy joints and those affected by OA. They conclude it is feasible that cartilage and bone function as a single unit, communicating via direct mechanical and biochemical signaling. It is unclear whether signaling molecules travel between the tissues, and if so, whether this is a cause or a result of OA. Further investigation of cartilage-bone communication may inform future OA therapies.

The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor (VDR), we examined their response to different concentrations of 25-hydroxy vitamin D₃ [25(OH)D₃] (100 or 500 nmol·L⁻¹) and 1,25-dihydroxy vitamin D₃ [1,25(OH)₂D₃] (0.1 or 0.5 nmol·L⁻¹) metabolites in cell cultures. Specifically, CD14+ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Tartrate-resistant acid phosphatase (TRAP) histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue (ex vivo) by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR (qRT-PCR) was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L⁻¹ of 25(OH)D₃ and 0.1–0.5 nmol·L⁻¹ of 1,25(OH)₂D₃, upregulating cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Osteoclast fusion transcripts transmembrane 7 subfamily member 4 (tm7sf4) and nuclear factor of activated T-cell cytoplasmic 1 (nfatc1) where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25(OH)D₃ and 1,25(OH)₂D₃ reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25(OH)₂D₃ on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.

Vitamin D: Bone resorption boosted by vitamin D derivatives

Derivatives of vitamin D can increase the number and the resorption activity of the osteoclast cells that break down bone tissue. A team led by Cameron Brown from the University of Oxford, UK, showed that osteoclasts from human bone tissue and from cell cultures express the receptor that is activated by vitamin D. The researchers stimulated the receptor with various concentrations of two vitamin D derivatives and saw an increase in osteoclast number and activity. They also observed a decrease in the levels of two proteins that cause fusion between osteoclasts, resulting in more but smaller cells. The findings suggest that the increase in bone mass density seen in people with osteoporosis who take vitamin D supplements may not be because of the suppression of osteoclasts as previously believed.

The transport of fluid, nutrients, and signaling molecules in the bone lacunar–canalicular system (LCS) is critical for osteocyte survival and function. We have applied the fluorescence recovery after photobleaching (FRAP) approach to quantify load-induced fluid and solute transport in the LCS in situ, but the measurements were limited to cortical regions 30–50 μm underneath the periosteum due to the constrains of laser penetration. With this work, we aimed to expand our understanding of load-induced fluid and solute transport in both trabecular and cortical bone using a multiscaled image-based finite element analysis (FEA) approach. An intact murine tibia was first re-constructed from microCT images into a three-dimensional (3D) linear elastic FEA model, and the matrix deformations at various locations were calculated under axial loading. A segment of the above 3D model was then imported to the biphasic poroelasticity analysis platform (FEBio) to predict load-induced fluid pressure fields, and interstitial solute/fluid flows through LCS in both cortical and trabecular regions. Further, secondary flow effects such as the shear stress and/or drag force acting on osteocytes, the presumed mechano-sensors in bone, were derived using the previously developed ultrastructural model of Brinkman flow in the canaliculi. The material properties assumed in the FEA models were validated against previously obtained strain and FRAP transport data measured on the cortical cortex. Our results demonstrated the feasibility of this computational approach in estimating the fluid flux in the LCS and the cellular stimulation forces (shear and drag forces) for osteocytes in any cortical and trabecular bone locations, allowing further studies of how the activation of osteocytes correlates with in vivo functional bone formation. The study provides a promising platform to reveal potential cellular mechanisms underlying the anabolic power of exercises and physical activities in treating patients with skeletal deficiencies.

Solute transport: Model reveals flow of fluid and nutrients in bone

A computational model of molecular movement within bone has revealed how mechanical forces impact bone formation. The findings help identify chemical and mechanical responses to physical activities in healthy individuals and point to ways that exercise could help people with skeletal deficiencies. Liyun Wang and colleagues from the University of Delaware, USA, created a three-dimensional model of a mouse leg bone to study how mechanical forces associated with exercise affect fluid flux and mechanical stimuli around osteocytes, which are embedded in bone and critical for bone health. The researchers validated their model using a previously developed imaging technique that can quantify load-induced transport of fluid, nutrients and signaling molecules, but only in the outer shell of bone. The new computational approach can be used to estimate fluid flows in any bone region, especially for the inside of bone which has been difficult to study.

ALKBH1 was recently discovered as a demethylase for DNA N⁶-methyladenine (N6-mA), a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells (MSCs) was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBH1-depleted MSCs also exhibited a restricted capacity for bone formation in vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region of ATF4, which subsequently silenced ATF4 transcription. In addition, restoring the expression of ATP by adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.

Bone development: DNA modification needed for stem cell differentiation

DNA modifications by the enzyme ALKBH1 is needed for stem cells to differentiate into bone-forming cells. Epigenetic gene regulation by the addition of chemical tags to the DNA base adenine was recently shown to be an important process in mammalian stem cells. ALKBH1 is a critical part of this newly discovered regulatory system. Shujuan Zou and colleagues from Sichuan University, Chengdu, China, investigated the role of this enzyme in bone development and found that elevated levels are present in human bone marrow-derived stem cells. ALKBH1 enhances gene expression by stripping methyl tags from adenine residues in the promoter region of the gene encoding an activating regulatory protein. The resulting elevated gene expression triggers a molecular cascade that drives differentiation of the stem cells into bone-forming cells.

Type II autosomal dominant osteopetrosis (ADO2), which is the most common form of osteopetrosis, is caused by heterozygous mutations in the chloride channel 7 (CLCN7) gene. The osteopetrosis of ADO2 has been attributed to hypofunctional osteoclasts. The mechanism underlying the abnormality in osteoclast function remains largely unknown. This study was designed to investigate gene mutations and osteoclast function in a case that was clinically diagnosed as ADO2. Genomic DNA was extracted from blood samples of this patient, and the 25 exons of CLCN7 were amplified. Peripheral blood from the ADO2 subject and a healthy age- and sex-matched control was used to evaluate osteoclastogenesis, osteoclast morphology, and bone resorption. Analysis of DNA from the patient showed a germline heterozygous missense mutation, c.1856C>T (p.P619L), in exon 20 of CLCN7. A similar homozygous mutation at this site was previously reported in a patient with autosomal recessive osteopetrosis. When cultured, the peripheral blood mononuclear cells (PBMCs) from the ADO2 patient spontaneously differentiated into mature osteoclasts in vitro. The ADO2 patient’s PBMCs formed enhanced, but heterogeneous, osteoclasts in both the presence and absence of macrophage-colony stimulating factor, and nuclear factor-ĸB ligand. Bone resorption was reduced in the ADO2 patient’s osteoclasts, which exhibited aberrant morphology and abnormal distribution of integrin a_vβ₃. Gene analysis found increased c-fos expression and reduced RhoA and integrin beta 3 expression in ADO2 cells. In conclusion, our data suggest that enhanced, heterogeneous osteoclast induction may be an intrinsic characteristic of ADO2.

Osteopetrosis: What makes bones too dense?

A mutation that reduces activity of bone-resorbing cells is responsible for a rare inherited disorder characterised by dense, brittle bones. Healthy bones undergo constant remodeling; osteoclasts resorb mature bone and osteoblasts generate new tissue. Patients with autosomal dominant osteopetrosis Type II (ADO2), the most common form of osteopetrosis, show impaired bone remodelling, resulting in overly dense, fragile bone tissue. No treatment is available, and although mutations in the chloride channel 7 gene (CLCN7) have been implicated, the mechanism underlying the disease remains unclear. Xijie Yu at Sichuan University and colleagues investigated gene mutations and osteoclast function in a recently diagnosed patient. The researchers found a single mutation of CLCN7 and higher than normal osteoclast generation; however, the osteoclasts were irregularly shaped and showed poor bone resorption. These results may help to identify treatments for osteopetrosis.

Presently, there is a high paucity of bone grafts in the United States and worldwide. Regenerating bone is of prime concern due to the current demand of bone grafts and the increasing number of diseases causing bone loss. Autogenous bone is the present gold standard of bone regeneration. However, disadvantages like donor site morbidity and its decreased availability limit its use. Even allografts and synthetic grafting materials have their own limitations. As certain specific stem cells can be directed to differentiate into an osteoblastic lineage in the presence of growth factors (GFs), it makes stem cells the ideal agents for bone regeneration. Furthermore, platelet-rich plasma (PRP), which can be easily isolated from whole blood, is often used for bone regeneration, wound healing and bone defect repair. When stem cells are combined with PRP in the presence of GFs, they are able to promote osteogenesis. This review provides in-depth knowledge regarding the use of stem cells and PRP in vitro, in vivo and their application in clinical studies in the future.

Tissue engineering: Building bone with stem cells and platelet-rich plasma

Stem cells combined with Platelet-Rich Plasma offer a way to regenerate bone lost due to disease or injury. In this review article, Gabriela Fernandes and Shuying Yang from the State University of New York, Buffalo, USA, discuss how tissue engineering could help overcome the shortage of suitable graft materials for patients with bone defects. The authors describe the various growth factors in platelet-rich plasma, and how the addition of adult stem cells, usually derived from bone marrow, can enhance bone formation. They provide an exhaustive summary of how this combination has been tested in cell culture, in animal models and in clinical trials. While the approach has shown promising, the authors suggest that new delivery techniques are needed that release the growth factors more slowly to fully promote the weeks-long process of bone regeneration.

Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells (BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1 (LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·L⁻¹ pargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.

Osteoporosis: histone-modifying therapy promotes bone formation

A drug that affects chemical modification of histones could enhance the bone-forming ability of stem cells. Yongsheng Zhou and colleagues from the Peking University School and Hospital of Stomatology in Beijing, China, treated human and mouse bone marrow-derived stem cells with pargyline, a decades-old blood-pressure drug that blocks an enzyme involved in stripping methyl tags from the histones. This enhanced the expression of bone-promoting genes, even under conditions designed to simulate the bone-thinning disease osteoporosis. The researchers showed that pargyline could also partially rescue or prevent osteoporosis in mouse models. The findings suggest that manipulating histone modification with pargyline or similar agents could improve bone therapies that involve tissue engineering with stem cells, or could be used as a clinical treatment for patients with osteoporosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, autosomal recessive genetic disease. This disease is characterized by the progressive calcification of soft tissues leading to symptoms of pressure and hyperphosphatemia but normal concentrations of serum calcium with or without an elevation of 1,25-dihydroxyvitamin D₃ levels.HFTC is caused by loss-of-function mutations in the GALNT3, FGF23 or KL genes. Here, we identified two novel mutations in the GALNT3 gene in a Chinese family with HFTC. Identification of a novel genotype in HFTC provides clues for understanding the phenotype–genotype relationships in HFTC and may assist not only in the clinical diagnosis of HFTC but also in the interpretation of the genetic information used for prenatal diagnosis and genetic counseling.

Genetics: New mutations found for rare joint disease

Two new mutations have been linked to a rare disease characterized by abnormal deposits of phosphate and calcium. Hyperphosphatemic familial tumoral calcinosis (HFTC) results from an increase in the levels of phosphate in the blood and a progressive calcification of the soft tissues around joints, most often in the hips, shoulders and elbows. The calcium deposits can form masses that impair movement. A team led by Jianmin Liu and Xiaoyi Ding from the Shanghai Jiao-Tong University School of Medicine, China, describe two novel mutations in a gene called GALNT3 in a pair of Chinese siblings with HFTC. These findings, the first from a Chinese family clinically diagnosed with HFTC and confirmed by genetic analysis, should help in future diagnoses and in understanding the molecular causes of the disease.

Osteoporosis is characterized by low bone mass and microarchitecture deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk. Evidence is accumulating for an important role of calcium deficiency as the process of aging is associated with disturbed calcium balance. Vitamin D is the principal factor that maintains calcium homeostasis. Increasing evidence indicates that the reason for disturbed calcium balance with age is inadequate vitamin D levels in the elderly. In this article, an overview of our current understanding of vitamin D, its metabolism, and mechanisms involved in vitamin D-mediated maintenance of calcium homeostasis is presented. In addition, mechanisms involved in age-related dysregulation of 1,25(OH)₂D₃ action, recommended daily doses of vitamin D and calcium, and the use of vitamin D analogs for the treatment of osteoporosis (which remains controversial) are reviewed. Elucidation of the molecular pathways of vitamin D action and modifications that occur with aging will be an active area of future research that has the potential to reveal new therapeutic strategies to maintain calcium balance.

Osteoporosis: Vitamin D and calcium balance

A greater understanding of how vitamin D regulates calcium would help the development of drugs to maintain bone health during aging. Age-related deterioration of bones leads to osteoporosis, and vitamin D deficiency in elderly people contributes to this process by reducing absorption of calcium. Sylvia Christakos and colleagues from the Rutgers, The State University of New Jersey, New Jersey Medical School, USA, have reviewed the role of vitamin D in maintaining calcium levels, and consider the potential of correcting vitamin D deficiency to treat osteoporosis. Treatment with vitamin D reduces the risk of fractures, and analogues of vitamin D are beneficial in osteoporosis, although this treatment is controversial. The authors conclude that further insight into the genetic and molecular mechanisms of vitamin D-mediated calcium regulation will enable the development of drugs that selectively target these mechanisms.

Biomedical applications of nanomaterials are exponentially increasing every year due to analogy to various cell receptors, ligands, structural proteins, and genetic materials (that is, DNA). In bone tissue, nanoscale materials can provide scaffold for excellent tissue repair via mechanical stimulation, releasing of various loaded drugs and mediators, 3D scaffold for cell growth and differentiation of bone marrow stem cells to osteocytes. This review will therefore highlight recent advancements on tissue and nanoscale materials interaction.

Biomaterials: Nanotechnology could help with bone repair

Nanoscale materials could help in bone tissue repair and regeneration in prosthetic surgery. In a review article, Nongyue He of Southeast University in Nanjing, China, and coworkers highlight recent advances in using nanotechnology to support the skeletal system. They describe the key properties for bone repair that nanoscale materials and composites must have, including biocompatibilityand bioabsorbability. Suitable nanomaterials can create an environment that promotes the growth of the various cell lineages needed for bone formation, including bone marrow stem cells and bone-supporting tissues. Nanoparticles are also being used to coat implants, in 3D-printed constructs and to induce magnetic fields to alter cell physiology. All these research strategies are designed to help overcome problems with conventional biomaterials that often fail to promote bone repair, leading to implant failure.