Differentiation and Proliferation of Periosteal Osteoblast Progenitors Are Differentially Regulated by Estrogens and Intermittent Parathyroid Hormone Administration

Ogita, Mami; Rached, Marie Therese; Dworakowski, Elzbieta; Bilezikian, John P.; Kousteni, Stavroula

doi:10.1210/en.2008-0369

Cited by 77 publications

(65 citation statements)

References 47 publications

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“…Indeed, these observations lead us to propose that PTH down-regulation of Sost in osteocytes is mediated by a two-step process [i.e., through PTH1R activation and cAMP/ERK signaling (probably a rapid and short term effect)], that is independent of Postn (20), then through Postn production and an autocrine/paracrine activation of integrin signaling, leading to a prolonged suppression of Sost expression. These latter observations are consistent with a direct activation of Wnt-β-catenin signaling by PTH in osteoblasts (28,29).…”

Section: Discussionsupporting

confidence: 87%

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Bonnet

Conway

Ferrari

2012

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

130

112

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Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn −/− and Postn +/+ mice to intermittent PTH. Compared with Postn +/+ , Postn −/− mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn −/− mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn −/− mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn −/− mice. In addition, primary osteoblasts from Postn −/− mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn −/− osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.

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Section: Discussionsupporting

confidence: 87%

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Bonnet

Conway

Ferrari

2012

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

130

112

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“…(14) When PTH is used intermittently as a treatment for osteoporosis, it similarly stimulates bone turnover increasing the amount of younger, less mineralized bone. (15) In contrast to hyperparathyroidism, however, this increased turnover seen with intermittent administration appears to favor anabolism, rather than catabolism, stimulating osteoblast progenitors, (16,17) inhibiting osteoblast apoptosis (18) and increasing bone density at the lumbar spine and hip while decreasing BMD at the distal radius. (19,20) When PTH therapy for osteoporosis is discontinued, spinal and hip gains in BMD are gradually lost and radial BMD increases.…”

Section: Discussionmentioning

confidence: 99%

Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism

Gafni

Guthrie

Kelly

et al. 2015

Journal of Bone and Mineral Research

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Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

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“…Indeed, mice exhibit profound sex-dependent differences in the pulsatility and amplitude of GH secretion that results in sexually dimorphic expression of GH target genes (48), providing one possible explanation for the gender specificity of the phenotypes the ΔGHR mice. Alternatively, it is known that osteoblasts that reside at the periosteal surface arise from precursors distinct from osteoblasts in the trabecular compartment, and evidence suggests these cells may have a differential response to PTH and estrogen (49). In addition, numerous studies, in both humans and animal models, have demonstrated that estrogen is predominantly responsible for periosteal expansion in males, converted from androgens by aromatase (50).…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes

et al. 2013

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Growth hormone (GH) exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 (IGF-1) in liver and skeletal tissues. To examine the requirement for the GH receptor (GHR) in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-1-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts (ΔGHR), which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female ∆GHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. By six weeks of age however, female ΔGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a "feminization" of bone geometry in 16 week-old mice, as observed by μCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male ΔGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater extent than previously appreciated in establishing the sexual dimorphism of the skeleton. Keywords: growth hormone; osteoblasts; knockout mice; bone; sexual dimorphism coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. During postnatal development, the activity and lifespan of osteoblasts is regulated by many local growth factors, cytokines, and systemic hormones (1,2). Among these, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exert anabolic activity, particularly during the rapid phases of bone acquisition that occur during the pubertal growth [22][23][24].In many tissues, GH actions are mediated by its ability to stimulate the production of IGF-1, a widely expressed polypeptide that bears homology to pro-insulin. IGF-1 signals primarily via the heterotetrameric type-1 IGF-1 receptor (IGF-1R) to trigger ERK and PI3K/Akt activation via SHC and insulin receptor substrate-1 and -2 (IRS-1/2) (25,26). IGF-1 is an important growth and survival factor for many cell types, including osteoblasts (27,28). IGF-1 ...

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Differentiation and Proliferation of Periosteal Osteoblast Progenitors Are Differentially Regulated by Estrogens and Intermittent Parathyroid Hormone Administration

Cited by 77 publications

References 47 publications

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism

Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes

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