Biologic therapies and bone loss in rheumatoid arthritis

Zerbini, Cristiano A. F.; Clark, Patricia; Méndez-Sánchez, Lucía; Pereira, Rosa Maria Rodrigues; Messina, Osvaldo Daniel; Uña, Claudia; Adachi, J.D.; Lems, Willem F.; Cooper, Cyrus; Lane, Nancy E.

doi:10.1007/s00198-016-3769-2

Cited by 157 publications

(137 citation statements)

References 117 publications

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“…67 The underlying mechanism most likely involves a TNF-a-dependent activation of osteoclastogenesis, 68,69 leading to osteopenia and bone resorption. Moreover, anti-TNF-a treatment also helps to prevent bone resorption in patients with RA and inflammatory bowel disease 30,31,70,71 and in inflammatory arthritis models in mice. 72,73 Interestingly, unilateral osteopenia adjacent to the injured knee can occur in patients following ACL injury, 67,74 raising questions about a possible role for TNF-a in this process.…”

Section: Discussionmentioning

confidence: 99%

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

Haxaire

Hakobyan

Pannellini³

et al. 2018

Blood

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Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic deficient mice ( mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-α levels in the affected joint of mice. Moreover, inactivation of TNF-α or iRhom2 in mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

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Section: Discussionmentioning

confidence: 99%

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

Haxaire

Hakobyan

Pannellini³

et al. 2018

Blood

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“…(38)(39)(40)(41) Additionally, use of anti-TNFa medication in patients with chronic inflammatory states, such as RA or AS, has been shown to decrease bone resorption, increase bone formation, prevent erosion formation in RA patients (which is due to osteoclast-mediated bone destruction), and decrease bone loss. (18,19) Although acute activation of NF-kB following stress or injury is critical for healing, (42) a sustained activation of TNFa and sTNFa-R1 level can potentially disturb the balance between osteoblast (cells involved in bone formation) and osteoclast (cells involved in bone resorption) activity through increased production RANKL, favoring bone resorption. (43) Cauley and colleagues (44) revealed that an elevated serum level of sTNFa-R1 was associated with increased incidence of fracture in men.…”

Section: Discussionmentioning

confidence: 99%

“…For clinical purposes, soluble TNFα‐R1 (sTNFα‐R1) with its long‐term bioavailability in stored serum is an optimal proxy of activated TNFα and a biomarker of systemic inflammation. Moreover, clinical data using TNF inhibitors in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (AS) have shown improvements in bone metabolite profiles and decreases in bone loss . Thus, we chose sTNFα‐R1 as a biomarker of inflammation for this study.…”

Section: Introductionmentioning

confidence: 99%

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Soluble Tumor Necrosis Factor Alpha Receptor 1, Bone Resorption, and Bone Mineral Density in the Year Following Hip Fractures: The Baltimore Hip Studies

Salimi

Shardell

Miller

et al. 2018

Journal of Bone and Mineral Research

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Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (trueβ^) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (trueβ^ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: trueβ^ = 0.76, p = 0.02; group 4: trueβ^ = 1.4, p < 0.001; women: group 3; trueβ^ = 0.67, p = 0.02; group 4: trueβ^ = 1.3, p = 0.004). Men in the highest sTNFα-R1 group had a greater decline in BMD compared to the lowest sTNFα-R1 group (2-month trueβ^ = −0.01, p = 0.01; 6-month: trueβ^ = −0.09, p = 0.001; 12-months: trueβ^ = −0.1, p < 0.001). An increasing rate of CTX-I was associated with a steeper decline in total hip BMD in those within higher sTNFα-R1 trajectory groups (p < 0.001). CTX-I was significantly increased with sTNFα-R1 in both sexes. CTX-I and the highest sTNFα-R1 trajectory were significantly associated with declines in total hip BMD in men. Interventions that reduce systemic inflammation should be explored to reduce bone resorption and prevent a decline in BMD after hip fracture.

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“…Many studies reported that blocking the function of Dkk-1 benefited bone maintenance and protected from systemic bone loss[5, 6]. Current opinions on osteoporosis realized that DKK1 level was associated with the pathophysiology of postmenopausal osteoporosis[7, 8], and with the inflammatory cytokines effects on bone mass[9, 10]. Ahmed et al showed postmenopausal women with significantly increased serum Dkk-1 had more severe osteoporosis, indicating that higher level of serum Dkk-1 might act as a biomarker for the development and severity of osteoporosis[7].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

et al. 2017

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Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3’UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/β-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.

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Biologic therapies and bone loss in rheumatoid arthritis

Cited by 157 publications

References 117 publications

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

Soluble Tumor Necrosis Factor Alpha Receptor 1, Bone Resorption, and Bone Mineral Density in the Year Following Hip Fractures: The Baltimore Hip Studies

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

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