Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

Toulis, Konstantinos; Anastasilakis, Athanasios D.; Polyzos, Stergios A.; Makras, Polyzois

doi:10.14310/horm.2002.1308

Cited by 26 publications

(15 citation statements)

References 199 publications

(166 reference statements)

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“…In summary, Lepr(-/-) mice showed both damaged osteoblastic bone formation and osteoclastic bone resorption that would result in low-turnover osteopathia, consistent with the low-turnover osteopenia observed in diabetic animals [45]. Since HPTHrP-(1-84) administration resulted in elevated extracellular calcium levels through increasing of renal calcium transport and osteoblastic bone formation without affecting bone resorption [10], we infer that the differences between half-life and functions of diverse PTHrP sequences might explain these diverse findings.…”

Section: Discussionsupporting

confidence: 77%

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

Liu

Wang

et al. 2015

Calcif Tissue Int

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Diabetic osteoporosis continues to surge worldwide, increasing the risk of fracture. We have previously demonstrated that haploinsufficiency of endogenous parathyroid hormone-related peptide (PTHrP) impairs fracture healing. However, whether an exogenous supply of PTHrP can repair bone damage and accelerate fracture healing remains unclear. This study aimed to assess the efficacy and safety of PTHrP in healing fractures. Standardized mid-diaphyseal femur fractures were generated in 12-week-old wild-type and leptin receptor null Lepr(-/-) mice. After administration of PTHrP for 2 weeks, callus tissue properties were analyzed by radiography, micro-computed tomography, histology, histochemistry, immunohistochemistry, and molecular biology techniques. At 2 weeks post-fracture, cartilaginous callus areas were reduced, while total callus and bony callus areas were increased in PTHrP-treated Lepr(-/-) animals and control wild-type mice, compared with vehicle-treated Lepr(-/-) mice. The following parameters were enhanced both in Lepr(-/-) mice after treatment with PTHrP and vehicle-treated wild-type animals, compared with vehicle-treated Lepr(-/-) mice: osteoblast numbers; tissue alkaline phosphatase (ALP) and Type I collagen immunopositive areas; mRNA levels of ALP, Type I collagen, osteoprotegerin, and receptor activator for nuclear factor-κ B ligand; protein levels of Runt-related transcription factor 2 and insulin-like growth factor-1; and the number and surface of osteoclasts. In conclusion, exogenous PTHrP by subcutaneous injection promotes fracture repair in Lepr(-/-) mice by increasing callus formation and accelerating cell transformation: upregulated osteoblastic gene and protein expression, increased endochondral bone formation, osteoblastic bone formation, and osteoclastic bone resorption. However, complete repair was not obtained in PTHrP-treated Lepr(-/-) mice as in control wild-type animals.

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Section: Discussionsupporting

confidence: 77%

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

Liu

Wang

et al. 2015

Calcif Tissue Int

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“…However, both PTH1-34) and PTH1-84) induce an excessive bone remodeling and carry the Bblack box^label of a 2-year prescription because of the long-term risk of osteosarcoma in preclinical studies in rats. When compared to the administration of PTH(1-34) or PTH(1-84), calcilytic drugs present advantages, namely, the ability to be orally bioavailable and modulate secretion of endogenous PTH, which ensures that PTH serum levels do not increase beyond the physiological range [88]. Thus, the main desirable characteristics present in calcilytic compounds are the ability to transiently increase PTH secretion, in order to obtain the anabolic effects of the hormone and lead to bone formation, drug specificity to the CaSR, and oral administration.…”

Section: Calcilytics: Effects On Bonementioning

confidence: 99%

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

et al. 2015

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Calcium released in the bone microenvironment during remodeling is a major factor in regulating bone cells. Osteoblast and osteoclast proliferation, differentiation, and apoptosis are influenced by local extracellular calcium concentration. Thus, the calcium-sensing properties of skeletal cells can be exploited in order to modulate bone turnover and can explain the bone anabolic effects of agents developed and employed to revert osteoporosis.

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“…Indeed, systemic PTH caused a decrease in serum phosphate levels only in wild type females, not in Ramp2 heterozygous females. While the long-term physiologic consequences of this are unclear, the established therapeutic roles of PTH and PTHrP in diseases like osteoporosis and cancer underscore the importance of understanding consequences of the RAMP2-PTH1R interaction in various organ systems in vivo [27–30]. …”

Section: Discussionmentioning

confidence: 99%

Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation

et al. 2017

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Receptor activity-modifying protein 2 (Ramp2) is a single-pass transmembrane protein that heterodimerizes with several family B G-protein coupled receptors to alter their function. Ramp2 has been primarily characterized in association with calcitonin receptor-like receptor (Calcrl, CLR), forming the canonical receptor complex for the endocrine peptide adrenomedullin (Adm, AM). However, we previously demonstrated that Ramp2+/- female mice display a constellation of endocrine-related phenotypes that are distinct from those of Adm+/- and Calcrl+/- mice, implying that RAMP2 has physiological functions beyond its canonical complex. Here, we localize Ramp2 expression in the mouse placenta, finding that Ramp2 is robustly expressed in the fetal labyrinth layer, and then characterize the effects of loss of Ramp2 on placental development. Consistent with the expression pattern of Ramp2 in the placenta, Ramp2-/- placentas have a thinner labyrinth layer with significantly fewer trophoblast cells secondary to a reduction in trophoblast proliferation. We also find that absence of Ramp2 leads to failed spiral artery remodeling unaccompanied by changes in the uterine natural killer cell population. Furthermore, we assess changes in gene expression of other RAMP2-associated G-protein coupled receptors (GPCRs), concluding that Ramp2 loss decreases parathyroid hormone 1 receptor (Pthr1) expression and causes a blunted response to systemic parathyroid hormone (PTH) administration in mice. Ultimately, these studies provide in vivo evidence of a role for RAMP2 in placental development distinct from the RAMP2-CLR/AM signaling paradigm and identify additional pathways underlying the endocrine and fertility defects of the previously characterized Ramp2 heterozygous adult females.

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Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

Cited by 26 publications

References 199 publications

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(−/−) Mice

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation

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