Parathyroid Hormone Receptor Signaling Induces Bone Resorption in the Adult Skeleton by Directly Regulating the RANKL Gene in Osteocytes

Ben-awadh, Abdullah N.; Delgado‐Calle, Jesús; Tu, Xiaolin; Kuhlenschmidt, Kali; Allen, Matthew R.; Plotkin, Lilian I.; Bellido, Teresita

doi:10.1210/en.2014-1046

Cited by 96 publications

(97 citation statements)

References 34 publications

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“…Our results are consistent with earlier studies demonstrating that elevated expression of Sost/sclerostin up-regulates RANKL (19,37) and increases osteoclasts (37). Expression of M-CSF is also elevated in daßcat Ot mice, consistent with our recent findings demonstrating that M-CSF is a downstream target of RANKL in osteocytes (38). Thus, the combination of elevated RANKL and M-CSF prevails over the increased expression of OPG, and resorption is then elevated in daßcat Ot mice.…”

Section: Discussionsupporting

confidence: 93%

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Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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236

237

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Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat Ot mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat Ot mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat Ot mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.osteocytes | canonical Wnt | beta-catenin | bone anabolism | notch signaling

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Section: Discussionsupporting

confidence: 93%

“…Similar high bone mass and high bone turnover phenotype is found in mice with activation of the PTH receptor in osteocytes (18,19,(38)(39)(40). Remarkably, however, the mechanisms underlying the skeletal phenotypes of these two mouse models are diametrically opposite.…”

Section: Discussionmentioning

confidence: 70%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

236

237

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“…On PTH treatment, osteocytes, which are the most abundant cells in adult bone, express RANKL via the PTH/parathyroid hormonerelated protein (PTHrP) receptor to induce osteoclastic bone resorption. 20,21) Osteocytes produce sclerostin, a negative regulator for bone formation, and PTH signaling suppresses the sclerostin production by inhibiting SOST gene expression in osteocytes. 11,12) Indeed, the mRNA expression of SOST was suppressed by PTH infusion at 4-h (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Optimal Duration of PTH(1–34) Infusion Is One Hour per Day to Increase Bone Mass in Rats

Shimizu

Noda

Joyashiki

et al. 2016

Biological & Pharmaceutical Bulletin

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Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (C ss , steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.Key words parathyroid hormone; bone mineral density; infusion; bone formation; bone marker; rat Intermittent administration of parathyroid hormone (PTH) is known to enhance bone mass in rats, while continuous infusion of PTH decreases bone mineral density (BMD) by increasing bone resorption.1) The contradictory phenomenon of PTH(1-34) action is caused by the dual effects of PTH on bone resorption and bone formation. To analyze the PTH action in bone, previous studies used an alzet infusion pump for programmed administrations or various dosing regimens of PTH(1-34) in rats, 2,3) but with this system it was difficult to identify the optimal duration of PTH treatment for anabolic and catabolic effects on bone.In previous studies, dosing rats with PTH(1-34) at 80 µg/kg elevated the serum level of PTH to 3800-18000 pg/mL, which is higher than the serum level of PTH (C max 160-360 pg/ mL) induced by therapeutic doses of PTH (0.3-0.4 µg/kg) in human.2-5) Furthermore, the pharmacokinetic profiles after intermittent subcutaneous (s.c.) administrations of PTH(1-34) in rats were shorter than those in human (T max and T 1/2 in rats: 15 min and 30 min; T max and T 1/2 in human: 30 min and 1 h). 4-6)These difficulties in establishing a relevant study mean that the optimal duration of PTH(1-34) to selectively exhibit anabolic effects on bone tissue has not been fully understood in either animals or humans...

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“…Unfortunately, the human response to PTH treatment is not universal and some patients have shown a bone catabolic effect (enhanced resorption) if too much PTH is administered or when treatment is stopped [57]. Enhanced osteoclast activity is also observed in constituently active PTH in osteocytes, in mice [58]. PTH targets osteoblast function to induce bone formation via the PTH type 1 receptor (PTH1R) which results in decreased Sost expression, increased WNT signaling, and increased bone formation, in wildtype mice [59].…”

Section: Current Osteoporosis Therapymentioning

confidence: 99%

Determining the Role of Sost and Sostdc1 During Fracture Healing

Yee¹

2016

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Parathyroid Hormone Receptor Signaling Induces Bone Resorption in the Adult Skeleton by Directly Regulating the RANKL Gene in Osteocytes

Cited by 96 publications

References 34 publications

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

The Optimal Duration of PTH(1–34) Infusion Is One Hour per Day to Increase Bone Mass in Rats

Determining the Role of Sost and Sostdc1 During Fracture Healing

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