Systemic Bone Loss Research Articles

New insights into IL-17/IL-23 signaling in ankylosing spondylitis (Review).

Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life.

Alterations in DNA methylation profiles in cancellous bone of postmenopausal women with osteoporosis.

Osteoporosis is characterized by systemic microarchitecture impairment and bone loss, which ultimately lead to fragility fractures. This disease is most common in older people, especially in postmenopausal women. Cancellous bone is affected by osteoporosis earlier than cortical bone, and DNA methylation microarray analysis of the hip cancellous bone of patients with osteoarthritis revealed differential methylation. In view of the important role of cancellous bone in bone development, we examined genome‐wide DNA methylation profiles in the cancellous bone from patients with postmenopausal osteoporosis versus healthy postmenopausal women using Illumina 850K methylation microarray analysis. Under a threshold of P < 0.05, we obtained a total of 8973 differentially methylated genes, such as SOX6, ACE, SYK and TGFB3. Under a threshold of P < 0.05 and |△β| > 0.2, a total of 17 and 34 key differentially methylated genes were further identified at the promoter region and cytosine‐ phosphate‐ guanine (CpG) islands (such as PRKCZ, GNA11 and COL4A1), respectively. PLEKHA2, PLEKHB1, PNPLA7, SCD, MGST3 and TSNAX were the most common differentially methylated genes at both the promoter region and CpG islands. Five important signaling pathways, including the calcium signaling pathway, the cyclic guanosine phospho‐protein kinase G (cGMP‐PKG) signaling pathway, endocytosis, the Rap1 signaling pathway and the AMPK signaling pathway were identified. Our study may be suitable as a basis for exploring the mechanisms underlying osteoporosis in postmenopausal women.

Alendronate loaded graphene oxide functionalized collagen sponge for the dual effects of osteogenesis and anti-osteoclastogenesis in osteoporotic rats

Graphene Oxide (GO)-related hydrogels have been extensively studied in hard tissue repair, because GO can not only enhance the mechanical properties of polymers but also promote osteogenic differentiation of mesenchymal stem cells. However, simple GO-related hydrogels are not ideal for the repair of osteoporotic bone defects as the overactive osteoclasts in osteoporosis. Alendronate (Aln) is known to inhibit osteoclasts and may bind to GO through covalent connection. Therefore, delivering Aln in GO-related hydrogels may be effective to repair osteoporotic bone defects. Here, we developed a control-released system which is constructed by collagen (Col)-GO sponges loaded with Aln (Col-GO-Aln) for osteoporotic bone defect repair. In vitro, Col-GO-Aln sponges prolonged the release period of Aln, and the sponge containing 0.05% (w/v) GO released Aln faster than sponge with 0.2% GO. Furthermore, tartrate-resistant acid phosphatase (TRAP) and F-actin staining demonstrated that Col-GO-Aln sponges effectively inhibited osteoclastogenesis of monocyte-macrophages. In vivo, micro-CT scan showed that the volume of newborn bone in defect site by 0.05% GO sponge was nearly three times larger than that of other groups. Moreover, the CT and histological examinations of rat femur proved that Col-GO-Aln sponges decreased the number of osteoclasts and suppressed the systemic bone loss in osteoporotic rats. These findings reveal that the application of GO as carriers of anti-osteoporosis drugs is a viable treatment for osteoporosis. The results also underscore the potential of GO-related hydrogels with Aln-releasing capacity for bone regeneration in osteoporosis.

Effect of Angiotensin II on Bone Erosion and Systemic Bone Loss in Mice with Tumor Necrosis Factor-Mediated Arthritis.

Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), which regulates the cardiovascular system. The RAS is reportedly also involved in bone metabolism. The upregulation of RAS components has been shown in arthritic synovial tissues, suggesting the potential involvement of Ang II in arthritis. Accordingly, in the present study, we investigated the role of Ang II in bone erosion and systemic bone loss in arthritis. Ang II was infused by osmotic pumps in tumor necrosis factor-transgenic (TNFtg) mice. Ang II infusion did not significantly affect the severity of clinical and histological inflammation, whereas bone erosion in the inflamed joints was significantly augmented. Ang II administration did not affect the bone mass of the tibia or vertebra. To suppress endogenous Ang II, Ang II type 1 receptor (AT1R)-deficient mice were crossed with TNFtg mice. Genetic deletion of AT1R did not significantly affect inflammation, bone erosion, or systemic bone loss. These results suggest that excessive systemic activation of the RAS can be a risk factor for progressive joint destruction. Our findings indicate an important implication for the pathogenesis of inflammatory bone destruction and for the clinical use of RAS inhibitors in patients with rheumatoid arthritis.

OP0040 ANTI-CITRULLINATED PROTEIN AUTOANTIBODIES ARE ASSOCIATED WITH ONGOING SYSTEMIC BONE LOSS IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS TREATED ACCORDING TO THE PRINCIPLES OF TREAT-TO-TARGET AND TIGHT-CONTROL

Background:Anti-citrullinated protein antibodies (ACPA) are a major risk factor for local and systemic bone loss in patients with rheumatoid arthritis (RA). We previously demonstrated that early RA patients at disease presentation already show reduced systemic bone mineral density (BMD) in association with ACPA-positivity (1). Whether the negative impact of ACPA on bone continues over time despite treatment institution is however unknown.Objectives:To investigate longitudinally the course of systemic bone loss in patients with early RA after institution of treatment with disease modifying anti-rheumatic drugs (DMARDs) according to the principles of treat-to-target and tight-control.Methods:The study population included 100 consecutive early RA patients (&lt;12 months of symptoms) recruited at our Early Arthritis inception cohort and already evaluated for systemic BMD at disease presentation before treatment start (1). After diagnosis, patients were prospectively followed-up at three-months intervals upon initiation of therapy with conventional synthetic DMARDs (methotrexate in 85% of the cases) aimed at the achievement of low disease activity (LDA, 28-joints disease activity score [DAS28] &lt;3.2). BMD was re-assessed after 24 months at the lumbar spine (L1-L4) and hip by the same dual X-ray absorptiometry (DXA) equipment used at baseline. Differences in BMD from baseline were evaluated in relation to demographic and clinical variables (listed in Table 1).Table.Predictors of bone mineral density changes over 24 months% change in BMDlumbar spinetotal hipfemoral neckrprprpAge0.2690.0080.0690.500.2580.01female gender0.0850.42-0.0230.54-0.1210.23menopause0.1370.200.0670.530.0870.41disease duration0.0740.470.0440.670.0160.87cumulative DAS280.0180.860.0020.870.0110.91time to LDA0.1420.16-0.0230.76-0.0440.66time to remission0.0350.74-0.0020.97-0.0110.91ACPA-0.2510.010.1260.22-0.1300.04RF-0.1130.270.1110.280.0010.99months of bisphosphonates0.3680.0030.1710.090.2910.04cumulative steroids-0.1430.16-0.0070.78-0.0090.93months of bDMARDs-0.1630.11-0.0540.48-0.0630.54Results:The study population was mainly composed of females (84%), of whom 64.3% were in post-menopause; the mean (SD) age was 57.4 (13.5) years. Median (IQR) symptoms duration before treatment start was 14 (9-24) weeks. Fourty-three percent of the patients was ACPA positive. After 24 months of treatment, LDA was achieved in 79% of the cases, and remission in 46%; 17.7% of the patients had initiated a biological DMARD. At DXA re-scanning, the BMD at the lumbar spine and total hip remained largely unchanged, whilst at the femoral neck decreased from 0.726 g/cm2 to 0.713 g/cm2 (mean difference [SD] -0.013 [0.056], p=0.02). Predictors of BMD changes at different sites are shown in Table 1. The cumulative dose of prednisone was borderline significant for more BMD loss at the lumbar spine. Cumulative disease activity did not significantly affect BMD changes. Rather, ACPA-positive patients had higher percent changes at both the lumbar spine and the femoral neck. In multivariable analyses, ACPA remained associated with more BMD loss even when adjusting for confounders (age, gender, cumulative steroids, bisphosphonate treatment) (r -0.126, p=0.04 at the lumbar spine; r -0.126, p=0.04 at the femoral neck).Conclusion:Treatment of patients with early RA according to treat-to-target strategies prevents systemic bone loss. However, despite optimal disease control, ACPA positivity continues to be associated with progressive decline in systemic BMD.

What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammatory conditions?

Osteochondroprogenitors are crucial for embryonic bone development and postnatal processes such as bone repair in response to fracture injury, and their dysfunction may contribute to insufficient repair of structural damage in inflammatory arthritides. In the fracture healing, the early inflammatory phase is crucial for normal callus development and new bone formation. This process involves a complex interplay of many molecules and cell types, responsible for recruitment, expansion and differentiation of osteochondroprogenitor populations. In inflammatory arthritides, inflammation induces bone resorption and causes insufficient bone formation, which leads to local and systemic bone loss. While bone loss is a predominant feature in rheumatoid arthritis, inflammation also induces pathologic bone formation at enthesial sites in seronegative spondyloarthropathies. Bone morphogenetic proteins (BMP) are involved in cell proliferation, differentiation and apoptosis, and have fundamental roles in maintenance of postnatal bone homeostasis. They are crucial regulators of the osteochondroprogenitor pool and drive their proliferation, differentiation, and lifespan during bone regeneration. In this review, we summarize the effects of inflammation on osteochondroprogenitor populations during fracture repair and in inflammatory arthritides, with special focus on inflammation-mediated modulation of BMP signaling. We also present data in which we describe a population of murine synovial osteochondroprogenitor cells, which are reduced in arthritis, and characterize their expression of genes involved in regulation of bone homeostasis, emphasizing the up-regulation of BMP pathways in early progenitor subset. Based on the presented data, it may be concluded that during an inflammatory response, innate immune cells induce osteochondroprogenitors by providing signals for their recruitment, by producing BMPs and other osteogenic factors for paracrine effects, and by secreting inflammatory cytokines that may positively regulate osteogenic pathways. On the other hand, inflammatory cells may secrete cytokines that interfere with osteogenic pathways, proapoptotic factors that reduce the pool of osteochondroprogenitor cells, as well as BMP and Wnt antagonists. The net effect is strongly context-dependent and influenced by the local milieu of cells, cytokines, and growth factors. Further elucidation of the interplay between inflammatory signals and BMP-mediated bone formation may provide valuable tools for therapeutic targeting.

Trabecular bone score, a new bone quality index, is associated with severe periodontitis.

The association between systemic bone loss and periodontitis remains unresolved; and the trabecular bone score (TBS) is a new index for assessing decreased bone quality. Therefore, this cross-sectional study investigated the association between TBS and severe periodontitis. Eight hundred and five Thai participants, aged 30 to 82 years, underwent bone quality assessment. Their mean TBS was calculated from dual-energy X-ray absorptiometry images at the L1 to L4 lumbar spine using TBS software. Each participant was classified as normal, partially degraded, or degraded TBS. Full-mouth periodontal examinations determined plaque score, probing depth, clinical attachment level (CAL), and the number of remaining teeth. The participants were classified as non-severe or severe periodontitis. Differences in periodontal parameters between the TBS groups were analyzed using one-way ANOVA. The association between TBS and severe periodontitis was assessed with multivariate binary logistic regression. For severe periodontitis, the additive interaction between TBS and oral hygiene status was also analyzed. The mean CAL was 0.9-mm higher in the degraded TBS group compared with the normal TBS group. Degraded TBS was associated with severe periodontitis with an adjusted odds ratio (OR) of 2.10 (95% confidence interval [CI]=1.03 to 4.26). The combination of degraded TBS and plaque score ≥80% increased the adjusted OR to 5.71 (95% CI=1.15 to 28.43). Degraded TBS is associated with severe periodontitis and has a synergistic effect with poor oral hygiene, suggesting monitoring decreased bone quality and good oral hygiene for promoting the periodontal-systemic health of these individuals.

Obesity potentially protects against systemic bone loss in patients with rheumatoid arthritis treated with tumour necrosis factor inhibitors.

We aimed to investigate how systemic bone metabolism was affected after 1 year of treatment with tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients. A total of 29 seropositive RA patients not treated for osteoporosis were enrolled and TNF inhibitors were administered for a year. Bone mineral density (BMD) at the lumbar spine, femur neck, and total hip was measured at baseline and 12 months after anti-TNF treatment. Blood samples were collected at baseline and 6 and 12 months after anti-TNF treatment and osteoclasts were cultured on bone slices. Weight was the strongest factor influencing systemic bone loss. Patients were categorised into two groups: obese (body mass index (BMI) ≥25 kg/m2) and non-obese (BMI <25 kg/m2). All patients showed decreased BMD at all sites. The obese group showed relatively little change in BMD, although the non-obese group showed significant decreases in BMD at all sites after 1 year of treatment with TNF inhibitors. Resorption pits created by osteoclasts decreased at 6 months and increased at 12 months in the non-obese group, while the obese group presented with steadily decreasing sizes of resorption pits at all-time points. Levels of receptor activator of nuclear factor kappa B ligand were significantly decreased at 12 months compared to baseline in the obese group, while they were increased in the non-obese group. One year of treatment with TNF inhibitors failed to halt systemic bone loss in RA patients, but obesity may have protective effects against bone loss.

Raloxifene administration enhances retention in an orthodontic relapse model.

Orthodontic relapse is a physiologic process that involves remodelling of the alveolar bone and principle periodontal ligament fibres. Raloxifene is an Food and Drug Administration (FDA)-approved selective oestrogen receptor modulator that inhibits systemic bone loss. In our study, we examined the effects of Raloxifene on alveolar bone modelling and orthodontic relapse in a rodent model. The efficacy of raloxifene was evaluated in 15-week-old male Wistar rats, 8 in each group (Control, Raloxifene, Raloxifene + 7-day relapse, Raloxifene + 14-day relapse) for a total of 42 days. All animals had 14 days of orthodontic tooth movement with a closed nickel-titanium coil spring tied from incisors to right first molar applying 5-8 gm of force. On the day of appliance removal, impression was taken with silicon material and the distance between first molar and second molar was filled with light-cured adhesive resin cement for retention phase. Raloxifene Retention, Raloxifene Retention + 7D, Raloxifene Retention + 14D groups received 14 daily doses of raloxifene (2.0 mg/kg/day) subcutaneously after orthodontic tooth movement during retention. After 14 days of retention, the retainer was removed and right first molar was allowed to relapse for a period of 14 days. Raloxifene injection continued for the Raloxifene + 14-day relapse group during relapse phase too. Control group received saline injections during retention. Animals were euthanized by CO2 inhalation. The outcome measure included percentage of relapse, bone volume fraction, tissue density, and histology analysis using tartrate-resistant acid phosphatase staining and determining receptor activator of nuclear factor-кB-ligand (RANKL) and osteoprotegerin expression. Raloxifene Retention + 14D group had significantly less (P < 0.05) orthodontic relapse when compared with other groups. There was a significant increase (P < 0.05) in bone volume fraction and tissue density in the Raloxifene Retention + 14D group when compared with other groups. Similarly, there was significant decrease in number of osteoclasts and RANKL expression in Raloxifene Retention + 14D group when compared with Raloxifene Retention + 7D group (P < 0.05). Raloxifene could decrease post-orthodontic treatment relapse by decreasing bone resorption and indirectly enhancing bone formation.

Enhanced dual function of osteoclast precursors following calvarial Porphyromonas gingivalis infection.

Background and objectiveExcessive osteoclast activity is a major characteristic of pathogenic bone loss in inflammatory bone diseases including periodontitis. However, beyond the knowledge that osteoclasts are differentiated from the monocyte/macrophage lineage and share common ancestry with macrophages and DC, the nature and function of osteoclast precursors are not completely understood. Furthermore, little is known about how osteoclast precursors respond to bacterial infection in vivo. We have previously demonstrated in vitro that the periodontal pathogen Porphyromonas gingivalis (Pg) plays a biphasic role on the receptor activator of nuclear factor kappa B ligand (RANKL)–induced osteoclast differentiation. In this study, we investigated the in vivo effect of Pg infection on the regulation of osteoclast precursors, using a mouse calvarial infection model.Methods and resultsC57BL/6 wild‐type and the myeloid differentiation factor 88 knockout (MyD88−/−) mice were infected with Pg by calvarial injection. Local and systemic bone loss, and the number and function of CD11b+c‐fms+ cells from bone marrow and spleen were analyzed. Our results show that Pg infection induces localized inflammatory infiltration and osteoclastogenesis, as well as increased number and osteoclastogenic potential of CD11b+c‐fms+ osteoclast precursors in the bone marrow and periphery. We also show that CD11b+c‐fms+RANK+ and CD11b+c‐fms+RANK− are precursors with similar osteoclastogenic and pro‐inflammatory potentials. In addition, CD11b+c‐fms+ cells exhibit an antigen‐specific T‐cell immune‐suppressive activity, which are increased with Pg infection. Moreover, we demonstrate that MyD88 is involved in the regulation of osteoclast precursors upon Pg infection.ConclusionsIn this study, we demonstrate an enhanced dual function of osteoclast precursors following calvarial Pg infection. Based on our findings, we propose the following model: Pg infection increases a pool of precursor cells that can be shunted toward osteoclast formation at the infection/inflammation sites, while at the same time dampening host immune responses, which is beneficial for the persistence of infection and maintenance of the characteristic chronic nature of periodontitis. Understanding the nature, function, and regulation of osteoclast precursors will be helpful for identifying therapeutic interventions to aid in the control and prevention of inflammatory bone loss diseases including periodontitis.

Periodontal therapeutics: Current host-modulation agents and future directions.

With the recognition in the 1960s and 1970s of the periodontopathic importance of the microbial biofilm and its specific anaerobic microorganisms, periodontitis was treated as an infectious disease (more recently, as a dysbiosis). Subsequently, in the 1980s, host‐response mechanisms were identified as the mediators of the destruction of the collagen‐rich periodontal tissues (gingiva, periodontal ligament, alveolar bone), and the periodontopathogens were now regarded as the "trigger" of the inflammatory/collagenolytic response that characterizes actively destructive periodontitis. Also at this time a new pharmacologic strategy emerged, entitled "host‐modulation therapy", based on 2 major findings: (1) that the ability of tetracycline antibiotics to inhibit periodontal breakdown was due (in large part) to their previously unrecognized ability to inhibit the host‐derived matrix metalloproteinases (notably, the collagenases, gelatinases, macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti‐inflammatory drugs, such as flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of periodontitis (however, the adverse effects of long‐term therapy precluded their development as safe and effective host‐modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat® [now generic] and Oracea®) and compositions of tetracyclines (notably chemically modified tetracycline‐3) as host‐modulator drugs for periodontitis, arthritis, cardiovascular and pulmonary diseases, cancer, and, more recently, for local and systemic bone loss in postmenopausal women. Identification of the cation‐binding active site in the tetraphenolic chemically modified tetracycline molecules drove the development of a new category of matrix metalloproteinase‐inhibitor compounds, with a similar active site, the biphenolic chemically modified curcumins. A lead compound, chemically modified curcumin 2.24, has demonstrated safety and efficacy in vitro, in cell culture, and in vivo in mouse, rat, rabbit, and dog models of disease. In conclusion, novel host‐modulation compounds have shown significant promise as adjuncts to traditional local therapy in the clinical management of periodontal disease; appear to reduce systemic complications of this all‐too‐common "inflammatory/collagenolytic" disease; and Oracea® is now commonly prescribed for inflammatory dermatologic diseases.

Bone Mineral Is More Heterogeneously Distributed in the Femoral Heads of Osteoporotic and Diabetic Patients: A Pilot Study.

ABSTRACTOsteoporosis is associated with systemic bone loss, leading to a significant deterioration of bone microarchitecture and an increased fracture risk. Although recent studies have shown that the distribution of bone mineral becomes more heterogeneous because of estrogen deficiency in animal models of osteoporosis, it is not known whether osteoporosis alters mineral distribution in human bone. Type 2 diabetes mellitus (T2DM) can also increase bone fracture risk and is associated with impaired bone cell function, compromised collagen structure, and reduced mechanical properties. However, it is not known whether alterations in mineral distribution arise in diabetic (DB) patients’ bone. In this study, we quantify mineral content distribution and tissue microarchitecture (by μCT) and mechanical properties (by compression testing) of cancellous bone from femoral heads of osteoporotic (OP; n = 10), DB (n = 7), and osteoarthritic (OA; n = 7) patients. We report that though OP cancellous bone has significantly deteriorated compressive mechanical properties and significantly compromised microarchitecture compared with OA controls, there is also a significant increase in the mean mineral content. Moreover, the heterogeneity of the mineral content in OP bone is significantly higher than controls (+25%) and is explained by a significant increase in bone volume at high mineral levels. We propose that these mineral alterations act to exacerbate the already reduced bone quality caused by reduced cancellous bone volume during osteoporosis. We show for the first time that cancellous bone mineralization is significantly more heterogeneous (+26%) in patients presenting with T2DM compared with OA (non‐DB) controls, and that this heterogeneity is characterized by a significant increase in bone volume at low mineral levels. Despite these mineralization changes, bone microarchitecture and mechanical properties are not significantly different between OA groups with and without T2DM. Nonetheless, the observed alterations in mineral heterogeneity may play an important tissue‐level role in bone fragility associated with OP and DB bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

A Novel, Tumor-Induced Osteoclastogenesis Pathway Insensitive to Denosumab but Interfered by Cannabidiol.

Bone metabolism is strictly regulated, and impaired regulation caused by hormonal imbalances induces systemic bone loss. Local bone loss caused by tumor invasion into bone is suggested to be induced by the generation of cytokines, which affect bone metabolism, by tumor cells. The major cause of systemic and local bone losses is excess bone resorption by osteoclasts, which differentiate from macrophages by receptor activator of nuclear factor kappa-B ligand (RANKL) or tumor necrosis factor-alpha (TNF-α). We previously found a novel pathway for tumor-induced osteoclastogenesis targeting osteoclast precursor cells (OPCs). Tumor-induced osteoclastogenesis was resistant to RANKL and TNF-α inhibitors. In the present study, we confirmed that exosomes derived from oral squamous cell carcinoma (OSCC) cells induced osteoclasts from OPCs. We also showed that the depletion of exosomes from culture supernatants of OSCC cells partially interfered with osteoclastogenesis, and cannabidiol, an innoxious cannabinoid without psychotropic effects, almost completely suppressed tumor-induced osteoclastogenesis. Osteoclastogenesis and its interference by cannabidiol were independent of the expression of nuclear factor of T cell c1 (NFATc1). These results show that osteoclastogenesis induced by OSCC cells targeting OPCs is a novel osteoclastogenic pathway independent of NFATc1 expression that is partially caused by tumor-derived exosomes and suppressed by cannabidiol.

Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis.

The Wnt signaling pathway plays a key role in several biological processes, such as cellular proliferation and tissue regeneration, and its dysregulation is involved in the pathogenesis of many autoimmune diseases. Several evidences support its role especially in bone complications of rheumatic diseases. In Rheumatoid Arthritis (RA), the Wnt signaling is implicated in systemic and localized bone loss, while available data of its role in Spondyloarthritis (SpA) are conflicting. In the last few decades, the quality of life of rheumatic patients has been dramatically improved by biological therapy, targeting cytokines involved in the pathogenesis of these diseases like tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-17. In this review, we reviewed the role of Wnt signaling in RA and SpA, focusing on the effect of biological therapy on this pathway and its possible clinical implications.

Osteoclast-Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss.

The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.

The Sintering Behaviour and Mechanical Properties of Hydroxyapatite - Based Composites for Bone Tissue Regeneration

The developement and regeneration of healthy bone tissue is a complex process that includes the interaction of different cell types and requires a set of coordinated processes. The loss of bone tissue may occur due to various reasons: surgical removal, bone trauma (i.e., fractures) or systemic bone loss (i.e., osteoporosis). When the natural bone tissue is destroyed, the regeneration capacity of the bone is not always satisfactory. The result consists therefore in many functional and structural aberrations. In order to improve and accelerate the healing process, bone substitutes have been developed. Hydroxyapatite has been widely used in bone applications due to its excellent biocompatibility, osteoconductivity and bioactivity [1,2]. The objective of this research is to obtain a new composite biomaterial that can be used as bone substitute. In this study, bovine hydroxyapatite obtained from freshly calcined bovine femur was used. The objective of this research is to obtain a new composite biomaterial that can be used as bone substitute. The experimental composite samples were obtained using bovine hydroxyapatite as matrix and tricalcium phosphate, respectively, magnesium oxide as reinforcement materials. The synthesis process of these new biomaterial composites, the effect of chemical composition, surface structure, chemical and phase composition as well as mechanical features have been investigated.

Loss of interleukin-10 exacerbates early Type-1 diabetes-induced bone loss.

Type-1 diabetes (T1D) increases systemic inflammation, bone loss, and risk for bone fractures. Levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are decreased in T1D, however their role in T1D-induced osteoporosis is unknown. To address this, diabetes was induced in male IL-10 knockout (KO) and wild-type (WT) mice. Analyses of femur and vertebral trabecular bone volume fraction identified bone loss in T1D-WT mice at 4 and 12 weeks, which in T1D-IL-10-KO mice was further reduced at 4 weeks but not 12 weeks. IL-10 deficiency also increased the negative effects of T1D on cortical bone. Osteoblast marker osterix was decreased, while osteoclast markers were unchanged, suggesting that IL-10 promotes anabolic processes. MC3T3-E1 osteoblasts cultured under high glucose conditions displayed a decrease in osterix which was prevented by addition of IL-10. Taken together, our results suggest that IL-10 is important for promoting osteoblast maturation and reducing bone loss during early stages of T1D.

An investigation of the bidirectional link between osteoporosis and periodontitis.

This study investigated whether periodontal disease is a predictor for systemic bone loss among elderly women. The utilization of FRAX® as a screening tool for severe periodontitis was also evaluated in this population. Current bone mineral density (BMD) for lumbar spine and proximal femur was used as an indicator of "bone status." Number of interdental sites with severe clinical attachment loss, frequency of bleeding on probing, and percentage of tooth loss due to periodontitis represented "periodontal disease" that was tested as a predictor of bone loss in a structural equation modeling analysis involving 110 participants. The intake of antiosteoporosis medication was considered in the analysis. Four other different criteria for periodontitis classification were also tested. FRAX® for major fracture was calculated without BMD, and with intervention threshold set by age. Longitudinally, BMD changes up to 10years were also obtained and checked for possible association with periodontitis. Periodontal disease was not a predictor for worse systemic bone status according to the different periodontal disease classifications, and was not associated with BMD changes. Antiosteoporosis medication directly predicted periodontal disease and systemic bone status. Women with FRAX® score above the intervention threshold had higher chance for periodontitis in more advanced stages: III/IV (OR = 1.13, 95% CI [1.04 to 1.22], p = 0.03). Periodontal disease did not constitute a predictor for reduced systemic bone density in the studied population of elderly women. On the other hand, FRAX® demonstrated to be a useful tool to suggest periodontal evaluation. Antiresorptive medication showed benefits on periodontal and bone status.

Implication of IL-17 in Bone Loss and Structural Damage in Inflammatory Rheumatic Diseases.

Proinflammatory cytokines play an important role in the systemic and focal bone loss associated with chronic inflammatory diseases. Targeting these cytokines with biologics and small molecules has led to a major improvement of the bone health of patients with inflammatory arthritis. Cytokines from the IL-17 family have been shown to be involved in the pathogenesis of several diseases such as spondyloarthritis, psoriatic arthritis, or psoriasis. IL-17A has been the first described and the most studied. The recent development of targeted therapies against IL-17A or its receptor and their efficacy has confirmed the importance of this cytokine in the development of inflammatory diseases. The aim of this review was to describe the effects of the IL-17 family and more particularly of IL-17A on bone and cartilage tissues. At the cellular level, IL-17A is proosteoclastogenic whereas its effects on osteoblasts depend on the stage of differentiation of these cells. In vivo, IL-17A is not required for normal bone homeostasis but plays an important role in bone loss notably in an ovariectomized mouse model of osteoporosis. Preliminary data from clinical trials showed a stabilisation of bone density in patients treated with anti-IL-17A antibodies. IL-17A plays a central role in the cartilage damage through the induction of collagenases and by decreasing the expression of their inhibitors in synergy with the other proinflammatory cytokines. The prevention of structural damage by anti-IL-17A therapies has been demonstrated in several pivotal clinical trials. Overall, blocking the IL-17A pathway seems to have a positive effect on the bone and cartilage damage observed in inflammatory arthritis. Differences and specificity of these effects compared to those already described with other biologics such as anti-TNF therapies remain to be explored.

Binding Immunoglobulin Protein (BIP) Inhibits TNF-α-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model.

ObjectiveThe association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro.Methods hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry.ResultsBiP‐treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c‐Fms and Receptor Activator of NF‐κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen–activated protein kinases, extracellular signal–regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c‐Fos and NFATc1. BiP directly inhibited TNF‐α– or Receptor Activator of NF–κB Ligand (RANKL)–induced NF‐κB nuclear translocation in THP‐1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways.ConclusionBiP combines an anti‐inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.