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Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients’ quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.

Osteoporosis, one of the serious health diseases, involves bone mass loss, bone density diminishing, and degeneration of bone microstructure, which is accompanied by a tendency toward bone fragility and a predisposition to fracture. More than 200 million people worldwide suffer from osteoporosis, and the cost of treating osteoporotic fractures is expected to reach at least $25 billion by 2025. The generation and development of osteoporosis are regulated by genetic factors and regulatory factors such as TGF-β, BMP, and FGF through multiple pathways, including the Wnt signaling pathway, the Notch signaling pathway, and the MAPK signaling pathway. Among them, the Wnt signaling pathway is one of the most important pathways. It is not only involved in bone development and metabolism but also in the differentiation and proliferation of chondrocytes, mesenchymal stem cells, osteoclasts, and osteoblasts. Dkk-1 and SOST are Wnt inhibitory proteins that can inhibit the activation of the canonical Wnt signaling pathway and block the proliferation and differentiation of osteoblasts. Therefore, they may serve as potential targets for the treatment of osteoporosis. In this review, we analyzed the mechanisms of Wnt proteins, β-catenin, and signaling molecules in the process of signal transduction and summarized the relationship between the Wnt signaling pathway and bone-related cells. We hope to attract attention to the role of the Wnt signaling pathway in osteoporosis and offer new perspectives and approaches to making a diagnosis and giving treatment for osteoporosis.

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.

A healthy skeleton depends on a continuous renewal and maintenance of the bone tissue. The process of bone remodeling is highly controlled and consists of a fine-tuned balance between bone formation and bone resorption. Biochemical markers of bone turnover are already in use for monitoring diseases and treatment involving the skeletal system, but novel biomarkers reflecting specific biological processes in bone and interacting tissues may prove useful for diagnostic, prognostic, and monitoring purposes. The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism and consequently the action of inhibitors of the pathway such as sclerostin and Dickkopf-related protein 1 (DKK1) have crucial roles in controlling bone formation and resorption. Thus, they might be potential markers for clinical use as they reflect a number of physiological and pathophysiological events in bone and in the cross-talk with other tissues in the human body. This review focuses on the clinical utility of measurements of circulating sclerostin and DKK1 levels based on preanalytical and analytical considerations and on evidence obtained from published clinical studies. While accumulating evidence points to clear associations with a number of disease states for the two markers, and thus, the potential for especially sclerostin as a biochemical marker that may be used clinically, the lack of standardization or harmonization of the assays still hampers the clinical utility of the markers.

Dickkopf-1 (Dkk-1) is a key regulator of bone remodeling in spondyloarthropathies. Nevertheless, data regarding its expression in cells of pathophysiologic relevance, such as mesenchymal stem cells (MSCs), are lacking. Herein, we aimed to address DKK1 gene expression and Wnt pathway activation in MSCs from patients with ankylosing spondylitis (AS) and explore the effect of IL-17 on MSCs with respect to DKK-1 expression and Wnt pathway activation. Primary MSCs were isolated from the bone marrow of the femoral head of two patients with AS and two healthy controls undergoing orthopedic surgery. MSCs were cultured for 7 days in expansion medium and for 21 days in osteogenic medium in the presence or absence of IL-17A. Gene expression of DKK-1 and osteoblastic markers was determined by RT-PCR. Alkaline phosphatase activity, alizarin red and Van Kossa staining were used to assess osteoblastic function and mineralization capacity. DKK-1 was significantly downregulated in MSCs and osteoblasts from patients with AS compared to controls. Moreover, MSCs and osteoblasts from AS patients displayed increased Wnt pathway activation and enhanced osteoblastic activity, as indicated by increased expression of osteoblast marker genes and alkaline phosphatase activity. IL-17 downregulated DKK-1 expression and increased osteoblastic activity and mineralization capacity. DKK-1 is underexpressed in MSCs from AS patients compared to controls, whereas IL-17 has an inhibitory effect on DKK-1 expression and stimulates osteoblastic function. These data may have pathogenetic and clinical implications in AS.

ObjectivesRheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging (dual-energy X-ray absorptiometry, DXA) and laboratory biomarkers in order to determine bone health and to study the effects of anti-tumor necrosis factor (TNF) biologics in RA and AS.Patients and methodsThirty-six RA and 17 AS patients undergoing 1-year etanercept (ETN) or certolizumab-pegol (CZP) therapy were studied. Bone density was assessed by DXA at baseline and after 12 months. Serum C-reactive protein (CRP), calcium, phosphate, parathyroid hormone (PTH), vitamin D3, osteocalcin, procollagen type I N-propeptide (P1NP), C-terminal telopeptide (βCTX), osteoprotegerin, sclerostin (SOST), Dickkopf-1 (DKK-1), soluble receptor activator nuclear kappa B ligand (sRANKL), and cathepsin K (cathK) levels were determined at baseline and after 6 and 12 months.ResultsTNF-α inhibition was clinically effective. Anti-TNF-α halted further bone loss over 1 year. In general, anti-TNF therapy significantly increased P1NP, SOST levels, and the P1NP/βCTX ratios, while decreased DKK-1 and CathK production at different time points in most patient subsets. In the full cohort and in RA, baseline and/or 12-month bone mineral density (BMD) at multiple sites exerted inverse relationships with CRP and βCTX, and positive correlation with SOST. In AS, L2-4 BMD after 1-year biologic therapy inversely correlated with baseline βCTX, while femoral neck BMD rather showed inverse correlations with CRP.ConclusionsAnti-TNF therapy slowed down generalized bone loss, in association with clinical improvements, in both diseases. TNF blockade may enhance bone formation and suppress joint destruction. Anti-TNF therapy may act inversely on DKK-1 and SOST. Independent predictors of BMD were SOST and βCTX in RA, whilst CRP in AS.Key Points• One-year anti-TNF therapy halted generalized bone loss in association with clinical improvement in arthritides.• Anti-TNF therapy may inversely act on DKK-1 and SOST.• Independent predictors of BMD were SOST and βCTX in RA, while CRP in AS.

Platelet-rich plasma (PRP) therapy has been considered as a promising treatment for androgenetic alopecia (AGA). The aim of the study was comparative evaluation of the clinical efficacy of PRP-therapy, minoxidil, and their combination in the treatment of men with AGA and to evaluate the effects of PRP on the proliferation of hair follicle (HF) cells in skin biopsy. Materials and Methods: The study involved 69 men who were divided into 3 groups who received PRP therapy, minoxidil, and their combination. The clinical efficacy of the therapy was evaluated by the dynamics of morphometric of hairs. To assess cell proliferation antibodies to β-catenin, CD34, Ki67, and to Dkk-1 were used. Results. PRP treatment was more effective than minoxidil therapy (p = 0.005). Complex therapy turned out to be more effective than minoxidil monotherapy (p < 0.0001) and PRP monotherapy (p = 0.007). After applying PRP the absolute and relative values of the β-catenin and CD34 expression area increased; an increase in Ki67+ index was also significant. Conclusions: PRP can be considered as a treatment option for AGA. Combined PRP and minoxidil use seems promising for the treatment of AGA. PRP increase in the proliferative activity of HF cells and improves hair morphology in patients with AGA.

The study aims to explore the role of the ERK signaling pathway in the crosstalk between Dkk-1 and TNF-α in MC3T3E1 pre-osteoblasts under cyclic tensile/compressive stress. A forced four-point bending system was used to apply cyclic uniaxial tensile/compressive strain (2000 μ, 0.5 Hz) to MC3T3E1 cells. Dkk-1 and TNF-α expression were upregulated in MC3T3E1 cells under compressive strain. Cell proliferation, the cell cycle, osteogenesis-related gene (Wnt5a, Runx2, Osterix) expression, β-catenin expression, and the p-ERK/ERK ratio were significantly enhanced, whereas apoptosis, the RANKL/OPG ratio, and TNF-α expression were significantly attenuated, by Dkk-1 silencing. Dkk-1 expression increased and the effects of Dkk-1 silencing were reversed when exogenous TNF-α was added. Mechanically, TNF-α crosstalked with Dkk-1 through ERK signaling in MC3T3E1 cells. ERK signaling blockade impaired Dkk-1-induced TNF-α expression and TNF-α-mediated Dkk-1 expression. Dkk-1 and TNF-α crosstalked, partially through ERK signaling, in MC3T3E1 cells under compressive/tensile strain, synergistically modulating various biological behaviors of the cells. These findings not only provide mechanical insight into the cellular events and molecular regulation of orthodontic tooth movement (OTM), but also aid the development of novel strategies to accelerate OTM.

Osteoarthritis is the most common musculoskeletal disorder. It primarily affects people in their mid-40s and older. As the disease progresses, degenerative changes occur in the synovial membrane, subchondral bone, and cartilage. Ultimately, the entire joint and its surrounding tissues become structurally and functionally impaired. Several sets of biochemical markers have been proposed to enable timely diagnosis and anticipate disease progression. However, only a few of these markers are routinely used to evaluate disease activity in subgroups. We conducted a cross-sectional, single-center cohort study of 72 patients with knee osteoarthritis. Diagnoses were established based on clinical data and radiological findings. We examined two Wnt/β-catenin signaling inhibitors, serum DKK-1 and sclerostin, and two bone/cartilage metabolic regulatory factors, RANKL and OPG, correlating these with disease activity and pain scores (WOMAC, VAS, and KOFUS), radiographic stage, inflammatory molecules and indices, and bone mineral density. DKK-1 levels were higher in the intensive pain group (VAS > 5) and positively correlated with the KOFUS throughout the study. This correlation was stronger in individuals with a BMI < 30. Serum DKK-1 levels were higher in patients with lower bone mineral density. No significant modifications in SOST, RANKL, or OPG levels were found in any of the above settings. In our patient cohort with mild-to-moderate knee osteoarthritis (OA), sclerostin, osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) were not related to pain or disease activity. In contrast, DKK-1 was an indicator of pain and low-grade flare-ups. Furthermore, DKK-1 was associated with the KOFUS and impaired bone turnover in non-obese subgroups. Confirming these relationships in larger groups of patients would contribute to more efficient use of DKK-1 in disease stratification algorithms.

Psoriatic arthritis (PsA) is a heterogenous systemic inflammatory disorder that affects peripheral joints and skin, but also causes inflammation at entheseal sites, digits (dactylitis) and the axial skeleton. Despite considerable advances, our understanding of the pathogenesis and management of PsA is hampered by its complex clinical expression. We enrolled patients who met the ClASsification for Psoriatic Arthritis (CASPAR) criteria for PsA (n = 17), and healthy controls (n = 13). The lipid profile, C-reactive protein (CRP) and Dickkopf-related protein 1 (DKK-1) circulating levels were measured for all subjects. For the patients with PsA, (1) the erosive character of the articular disease was assessed by a musculoskeletal ultrasound and (2) the cardiovascular risk was evaluated using the Systematic Coronary Risk Evaluation (SCORE) chart and the ultrasound measurement of the carotid intima-media thickness. A higher titer of serum DKK-1 was associated with the presence of erosions (p < 0.005) and the cIMT correlated with DKK-1 levels in patients with PsA (r = 0.6356, p = 0.0061). Additionally, we observed a positive correlation between increased cIMT and CRP (r = 0.5186, p = 0.0329). Our results suggest that DKK-1 could be used as an early biomarker for the erosive character of the articular disease and for the assessment of the cardiovascular risk in PsA patients.