The Therapeutic Potential of the Wnt Signaling Pathway in Bone Disorders

Wagner, Eric R.; Zhu, Guoqiang; Zhang, Bingqiang; Luo, Qi; Shi, Qiong; Huang, Enyi; Gao, Yanhong; Gao, Jian‐Li; Kim, Stephanie H.; Rastegar, Farbod; Yang, Ke; He, Bai‐Cheng; Chen, Liang; Zuo, Guo‐Wei; Bi, Yang; Su, Yuxi; Luo, Jinyong; Luο, Xingguang; Huang, Jiayi; Deng, Zhongliang; Reid, Russell R.; Luu, Hue H.; Haydon, Rex C.; He, Tong‐Chuan

doi:10.2174/1874467211104010014

Cited by 56 publications

(33 citation statements)

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“…Specific human pathologies of bone such as osteoporosis pseudoglioma syndrome, sclerosteosis and van Buchem's disease have been associated with aberrant Wnt signaling; these discoveries have triggered further research of the Wnt signaling pathway in bone biology [Monroe et al 2012]. Understanding the role of Wnt signaling in bone disorders has not only helped elucidate the pathogenesis of those disorders but has also led to the development of potential therapeutic avenues to treat the disorders [Hoeppner et al 2009;Wagner et al 2011]. In particular, the development of neutralizing antibodies targeting endogenous Wnt Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim

Liu

Wang

et al. 2013

Therapeutic Advances in Musculoskeletal

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Abstract:The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.

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Section: Introductionmentioning

confidence: 99%

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim

Liu

Wang

et al. 2013

Therapeutic Advances in Musculoskeletal

Self Cite

289

239

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“…(1) Wnt/b-catenin pathway activation expands osteoprogenitor cells while reducing osteoblast apoptosis, resulting in bone anabolism. (2) Sclerostin regulates Wnt/b-catenin and influences bone mass. (2) Sclerostin mutations cause significantly increased bone mass in sclerosteosis and van Buchem's disease.…”

Section: Introductionmentioning

confidence: 99%

“…(2) Sclerostin regulates Wnt/b-catenin and influences bone mass. (2) Sclerostin mutations cause significantly increased bone mass in sclerosteosis and van Buchem's disease. (3)(4)(5) Animal studies demonstrated that antisclerostin antibodies increase bone density and bone strength.…”

Section: Introductionmentioning

confidence: 99%

High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: The center of excellence for osteoporosis research study

Ardawi

Rouzi

Al-Sibiani

et al. 2012

Journal of Bone and Mineral Research

128

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Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low circulating sclerostin levels cause high bone mass. We hypothesized that postmenopausal women with increased sclerostin levels have a greater risk for osteoporosis-related fractures. We examined the association between circulating sclerostin together with bone turnover markers and osteoporosis-related fracture risk in 707 postmenopausal women, in a population-based study with a mean follow-up period of 5.2 AE 1.3 years. Multivariate Cox proportional hazards regression models were used to analyze fracture risk, adjusted for age, body mass index, and other confounding risk factors. High sclerostin levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the relative fracture risk was more than sevenfold among postmenopausal women for each 1-SD increment increase in sclerostin level. Women in the highest quartile of sclerostin levels had about a 15-fold increase in fracture risk. Results were similar when we compared sclerostin at the 1-year visit to an average of two to three annual measurements. Fracture risk attributable to sclerostin levels was 56.6% in the highest quartile. Only high levels of bone resorption markers (plasma cross-linked C-terminal telopeptide of type 1 collagen [p-CTx], urinary CTx [u-CTx], and urinary N-telopeptide of type 1 collagen [u-NTx]) were predictive of osteoporosis-related fractures but at much lower hazard ratio (HR) values than that of serum sclerostin. Associations between sclerostin levels and fracture risk were independent of bone mineral density and other confounding risk factors. High sclerostin levels are a strong and independent risk factor for osteoporosis-related fractures among postmenopausal women. ß

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“…To address the pressing need for new therapies that are both anabolic and antiosteoclastic [7,[9][10][11], promising new agents that increase Wnt/β-catenin activity are in development. Wnt/β-catenin signaling plays a key role in directing stem cell differentiation to osteoblasts and in inhibiting osteoclast activity [12,13]. In addition, decreased Wnt/β-catenin signaling has been implicated in osteoporosis [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, decreased Wnt/β-catenin signaling has been implicated in osteoporosis [14,15]. However, because recombinant Wnts are difficult to produce and deliver, most approaches to increase Wnt/β-catenin signaling involve the blockade of naturally occurring Wnt antagonists via antibodies (e.g., anti-DKK1 or anti-Sclerostin antibodies) [12,13] to functionally 'de-repress' Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%