Does osteocytic SOST suppression mediate PTH bone anabolism?

doi:10.1016/j.tem.2009.12.002

Trends in Endocrinology & Metabolism

Volume 21, Issue 4, April 2010, Pages 237-244

https://doi.org/10.1016/j.tem.2009.12.002 Get rights and content

Parathyroid hormone (PTH) has bone anabolic activity when administered intermittently, affecting cells of the osteoblastic lineage at various stages, yet much remains to be learned about precisely how PTH promotes osteoblastic bone formation. Recent discoveries revealed that PTH causes transcriptional suppression of the osteocyte marker gene SOST, which encodes the potent secreted bone formation inhibitor, sclerostin. This review addresses whether osteocytes, terminally differentiated cells of the osteoblastic lineage, which are entrapped within the mineralized bone matrix, contribute to PTH-induced bone formation responses via regulation of sclerostin levels, and discusses recent evidence on how the bone anabolic responses elicited by intermittent PTH treatment or by sclerostin inhibition overlap and diverge.

Section snippets

Intermittent parathyroid hormone (PTH) treatment is bone anabolic, whereas continuous treatment is bone catabolic

PTH is currently the only anabolic bone treatment option for patients with low bone mass conditions such as severe osteoporosis (OP) (Box 1). It has received much attention in recent years because of the finding that intermittent treatment (i.e. daily injection) causes a significant increase in bone mass 1, 2, 3. The intact hormone PTH (1–84) and its N-terminal fragment (1–34) have been developed as treatments for established osteoporosis. Nonetheless, despite PTH being a well-recognized bone

Osteocytes express PTH1R and secrete the bone formation inhibitor, sclerostin

Osteoblasts differentiate from mesenchymal bone marrow progenitor cells into bone forming cells that reside on the bone surface and deposit new bone matrix. A small fraction of osteoblasts further differentiates into osteocytes, terminally differentiated cells of the osteoblastic lineage, which represent >90% of all bone cells in the adult skeleton [17]. They reside within lacunae, small cavities within the mineralized bone matrix, and extend long, thin cellular protrusions termed dendrites,

PTH suppresses osteocytic Sost expression

The localization and abundance of osteocytes within bone, their expression of PTH1R and their ability to secrete the potent bone formation inhibitor sclerostin indicate their potential role as important regulators of bone formation. This hypothesis is supported by the findings that PTH suppresses Sost transcription in vitro 32, 33. Moreover, PTH treatment decreases Sost expression in vivo 32, 33, 34, resulting in fewer numbers of osteocytes expressing sclerostin 33, 34. Sost expression was

PTH-induced Sost inhibition contributes to PTH bone anabolic action in vivo

Recently, the role of PTH signaling in osteocytes in vivo was addressed in mice overexpressing a constitutively active PTH1R variant selectively in osteocytes, mimicking part of the effects triggered by continuous systemic PTH exposure [39]. In these mice, Sost expression is suppressed by about 80% and consistently, the number of sclerostin positive osteocytes is dramatically reduced. These mice further display a bone overgrowth phenotype characterized by elevated bone turnover caused by

PTH signaling activates canonical Wnt signaling

Transgenic mice selectively expressing constitutively active PTH1R in osteocytes display decreased Sost expression and increased canonical Wnt signaling [39]. As described, sclerostin is currently speculated to function as a secreted inhibitor of canonical Wnt/β-catenin signaling by binding to Lrp5 and Lrp6 Wnt co-receptors, preventing their association with the Wnt-Frizzled (Fzd) receptor complex [28] (Figure 2a). Interestingly, simultaneous deletion of Lrp5 abolished the increased bone mass

Intermittent PTH treatment and sclerostin inhibition: two converging and diverging bone anabolic principles

It is worth pointing out that bone anabolism induced by intermittent PTH treatment or sclerostin inhibition overlap in several, but not in all aspects. The bone forming effects of an anti-sclerostin antibody in rodents [53] resemble in some ways those of high-dose intermittent PTH treatment [54]. Either anabolic agent increases both the extent of bone forming surfaces and osteoblastic bone matrix synthesis. Likewise, all skeletal envelopes respond to bone anabolic intermittent PTH treatment and

Concluding remarks

PTH exerts complex and only partially elucidated cellular and molecular actions in bone, directly affecting bone marrow stromal cells and osteoblasts at all stages of their life cycle. In addition, PTH indirectly regulates osteoclast differentiation and activity through cells of the osteoblastic lineage via various paracrine cytokines and growth factors. Recent studies in mice demonstrate that bone anabolic pathways induced by PTH or sclerostin inhibition partially overlap, because loss or gain

Acknowledgements

We thank Frederic Bassilana and Klaus Seuwen for critically reviewing the manuscript.

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Prolonged disuse and substantial mechanical unloading are particularly damaging to skeletal integrity. Preclinical studies in rodents and clinical studies have highlighted the need for potent bone anabolic drugs to counteract disuse-induced osteopenia. The aim of present study was to compare the efficacy of romosozumab (Scl-Ab) and abaloparatide (ABL), alone or in combination, to prevent botulinum toxin (BTX) induced bone loss in a rat model. Eighty female Wistar rats were divided into the following six groups: 1. Baseline (n = 12); 2. Control (Ctrl) (n = 12); 3. BTX (n = 12); 4. BTX + Scl-Ab (n = 16); 5. BTX + ABL (n = 12); and 6. BTX + Scl-Ab + ABL (n = 16). Disuse was achieved by injecting 4 IU BTX into the hind limb musculature at study start. Scl-Ab (25 mg/kg) was injected s.c. twice weekly, while ABL (80 μg/kg) was injected s.c. five days a week for four weeks. Hind limb disuse dramatically decreased muscle mass and skeletal integrity and deteriorated the cortical morphology and trabecular microstructure. Treatment with Scl-Ab alone prevented most of the adverse cortical and trabecular effects of disuse, while ABL monotherapy mainly attenuated the disuse-induced loss of femoral areal bone mineral density (aBMD). Moreover, the combination of Scl-Ab and ABL not only counteracted most of the negative skeletal effects of unloading, but also increased aBMD (+10% and +20%), epiphyseal trabecular bone volume fraction (BV/TV) (+25% and +73%), and metaphyseal bone strength (+18% and +30%) significantly above that of Scl-Ab or ABL monotherapy, respectively. The potent and additive osteoanabolic effect of Scl-Ab and ABL, when given in combination, is highly intriguing and underlines that an osteoanabolic bone gain can be maximized by utilizing two pharmaceuticals targeting different cellular signaling pathways. From a clinical perspective, a combination treatment may be warranted in patients where the osteoanabolic effect of either monotherapy is not sufficient, or if a dose-reduction is required due to adverse effects.
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The parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PPR) is a class 2G-protein-coupled receptor that serves to control, via PTH, blood levels of ionized calcium and phosphate, and, via PTHrP, the development of several tissues, including the skeleton. The PPR is expressed in bone and kidney cells, the key target sites of PTH, and in differentiating mesenchymal cells, the target sites of PTHrP. Upon ligand binding, the PPR couples to stimulatory G proteins and the cAMP signaling pathway. Defects in the PPR system are associated with several diseases of bone development and calcium homeostasis, and PTH(1−34) and PTH(1−84) are now being used to treat osteoporosis. Further development of these peptide ligands could lead to improved treatments for this and related diseases of bone and mineral ion metabolism.
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Parathyroid hormone is an essential regulator of extracellular calcium and phosphate. PTH enhances calcium reabsorption while inhibiting phosphate reabsorption in the kidneys, increases the synthesis of 1,25-dihydroxyvitamin D, which then increases gastrointestinal absorption of calcium, and increases bone resorption to increase calcium and phosphate. Parathyroid disease can be an isolated endocrine disorder or part of a complex syndrome. Genetic mutations can account for diseases of parathyroid gland formulation, dysregulation of parathyroid hormone synthesis or secretion, and destruction of the parathyroid glands. Over the years, a number of different options are available for the treatment of different types of parathyroid disease. Therapeutic options include surgical removal of hypersecreting parathyroid tissue, administration of parathyroid hormone, vitamin D, activated vitamin D, calcium, phosphate binders, calcium-sensing receptor, and vitamin D receptor activators to name a few. The accurate assessment of parathyroid hormone also provides essential biochemical information to properly diagnose parathyroid disease. Currently available immunoassays may overestimate or underestimate bioactive parathyroid hormone because of interferences from truncated parathyroid hormone fragments, phosphorylation of parathyroid hormone, and oxidation of amino acids of parathyroid hormone.
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Research in human genetic disorders has often led to significant progress in biomedical research. One such example is the discovery that in humans, loss- and gain-of-function mutations in components of the Wnt signaling pathway, such as LRP5 and Sclerostin, result in dramatic bone phenotypes. Over the last two decades, significant progress has been made in our understanding of the link between bone mass and Wnt signaling and it is now evident that Wnt signaling is central to bone development and skeletal homeostasis and that flaws in this pathway lead to altered bone mass.
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Effects of Zhuang Gu Zhi Tong Formula on Wnt/β-catenin Osteoporosis Pathway Antagonist SOST in Osteoporosis
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To observe the effects of Zhuang Gu Zhi Tong Formula (ZGZTF) on antagonist SOST in canonical Wnt/β-catenin signaling pathway in osteoporosis.
We analyzed the differential genes of patients with osteoporosis and normal subjects from the GEO database and then found SOST with specific expression. We analyzed SOST as an antagonist of the Wnt signaling pathway by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Then we studied the effect of ZGZTF on SOST in Wnt signaling pathway. Osteoporosis model was induced by ovariectomy (OVX) in 8-week-old female Sprague–Dawley (SD) rats. After 12 weeks of treatment with ZGZTF by intragastric administration, the rats were put to death in batch. The changes of alkaline phosphatase (ALP), bone gla protein (BGP) and estradiol (E2) in serum were determined, and bone mineral density (BMD) and histomorphology of right femur were observed. Biomechanics of lumbar vertebra were measured, and the expression of SOST, Wnt3a, β-catenin, LRP5, Runx2, Osx and their mRNA involving the canonical Wnt/β-catenin signaling pathway were detected by Western blot, RT-PCR and Immunohistochemical analysis. All data were analyzed by SPSS 22.0.
Twelve weeks of treatment with ZGZTF could significantly decrease the level of ALP and BGP in serum, increase the BMD of femurs, and improve the biomechanical capability of vertebral body in maximum loading and elastic modulus. Concerning histomorphology, we found ordered arrangement of trabeculae, slightly thinning of trabeculae and none obvious slight fractures in femurs after 12 weeks of treatment with ZGZTF. The expression of LRP5, β-catenin, Runx2 and Osx involved in the canonical Wnt/β-catenin signaling pathway was significantly up-regulated in the presence of ZGZTF, and the expression of SOST in this pathway was down-regulated.
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The very large economic and social burdens of fracture-related complications make rapid fracture healing a major public health goal. The role of parathyroid hormone (PTH) in treating osteoporosis is generally accepted, but the effect of PTH on fracture healing is controversial. This meta-analysis was designed to investigate the efficacy and safety of PTH in fracture healing. The EMBASE, PubMed, and Cochrane Library databases were systematically searched from the inception dates to April 26, 2018. The primary randomized clinical trials comparing PTH treatment for fracture healing with placebo or no treatment were identified. We did not gain additional information by contacting the authors of the primary studies. Two reviewers independently extracted the data and evaluated study quality. This meta-analysis was executed to determine the odds ratio, mean difference, standardized mean difference, and 95% confidence intervals with random-effects models. In total, 8 randomized trials including 524 patients met the inclusion criteria. There were significant differences in fracture healing time, pain relief and function improvement. There were no significant differences in the fracture healing rate or adverse events, including light-headedness, hypercalcemia, nausea, sweating and headache, except for slight bruising at the injection site. We determined that the effectiveness and safety of PTH in fracture healing is reasonably well established and credible.

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Trends in Endocrinology & Metabolism

ReviewDoes osteocytic SOST suppression mediate PTH bone anabolism?

Section snippets

Intermittent parathyroid hormone (PTH) treatment is bone anabolic, whereas continuous treatment is bone catabolic

Osteocytes express PTH1R and secrete the bone formation inhibitor, sclerostin

PTH suppresses osteocytic Sost expression

PTH-induced Sost inhibition contributes to PTH bone anabolic action in vivo

PTH signaling activates canonical Wnt signaling

Intermittent PTH treatment and sclerostin inhibition: two converging and diverging bone anabolic principles

Concluding remarks

Acknowledgements

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Endocr. Rev.

Parathyroid Hormone as an anabolic skeletal therapy

Drugs

Effects of parathyroid hormone on wnt signaling pathway in bone

J. Cell Biochem.

Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy

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Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass

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Short-term changes in bone turnover markers and BMD Response to parathyroid hormone in postmenopausal women with osteoporosis

J. Clin. Endocrinol. Metab.

Molecular profile of catabolic versus anabolic treatment regimens of parathyroid hormone (PTH) in rat bone: an analysis by DNA microarray

J. Cell Biochem.

Osteocytes as dynamic multifunctional cells

Ann. N. Y. Acad. Sci.

Review
Does osteocytic SOST suppression mediate PTH bone anabolism?