Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

Lanske, Beate; Amling, Michael; Neff, Lynn; Guiducci, Jennifer; Baron, Roland; Kronenberg, Henry M.

doi:10.1172/jci6629

Cited by 223 publications

(140 citation statements)

References 36 publications

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“…Differences in skeletal development of long bones between BGsKO and control mice became most apparent on day E16.5 when it was clear that primary spongiosa in BGsKO mice had less immature bone matrix (osteoid) area, indicative of slower bone formation in this region, which resulted in less metaphyseal trabecular bone. Similar findings have been observed in PPR (29) and PTH (6) but not in PTHrP (29) knock-out mice, suggesting that PTH is a major prenatal stimulator of bone formation within the primary spongiosa. PTH is also known to act as an anabolic agent for trabecular bone (30) and, for this reason, is presently used as a therapy for osteoporosis.…”

Section: Discussionsupporting

confidence: 81%

“…PTH (6) and PPR (29) knock-out models also had reduced trabecular and increased cortical bone, whereas mice with osteoblast-specific expression of an activated PPR had the opposite effects on trabecular and cortical bone (7). Moreover, patients with primary hyperparathyroidism with excess circulating PTH levels tend to have a greater loss of cortical bone and relative sparing of trabecular bone (35).…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of the G-protein α-Subunit Gsα in Osteoblasts Leads to Differential Effects on Trabecular and Cortical Bone

Sakamoto¹,

Chen²,

Nakamura

et al. 2005

Journal of Biological Chemistry

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The G-protein ␣-subunit G s ␣ is required for the intracellular cAMP responses to hormones and other agonists. G s ␣ is known to mediate the cAMP response to parathyroid hormone and other hormones and cytokines in bone and cartilage. To analyze the in vivo role of G s ␣ signaling in osteoblasts, we developed mice with osteoblast/osteocyte-specific G s ␣ deficiency (BGsKO) by mating G s ␣-floxed mice with collagen I␣1 promoter-Cre recombinase transgenic mice. Early skeletal development was normal in BGsKO mice, because formation of the initial cartilage template and bone collar was unaffected. The chondrocytic zones of the growth plates also appeared normal in BGsKO mice. BGsKO mice had a defect in the formation of the primary spongiosa with reduced immature osteoid (new bone formation) and overall length, which led to reduced trabecular bone volume. In contrast, cortical bone was thickened with narrowing of the bone marrow cavity. This was probably due to decreased cortical bone resorption, because osteoclasts were markedly reduced on the endosteal surface of cortical bone. In addition, the expression of alkaline phosphatase, an early osteoblastic differentiation marker, was normal, whereas the expression of the late osteoblast differentiation markers osteopontin and osteocalcin was reduced, suggesting that the number of mature osteoblasts in bone is reduced. Expression of the osteoclast-stimulating factor receptor activator of NF-B ligand was also reduced. Overall, our findings have similarities to parathyroid hormone null mice and confirm that the differential effects of parathyroid hormone on trabecular and cortical bone are primarily mediated via G s ␣ in osteoblasts. Osteoblast-specific G s ␣ deficiency leads to reduced bone turnover.1 is a ubiquitously expressed G-protein ␣-subunit that couples receptors to adenylyl cyclase and is required for receptor-stimulated cAMP generation (1). cAMP is an important second messenger in osteoblasts for several hormones and other extracellular factors, such as parathyroid hormone (PTH) and prostaglandin E 2 . Both PTH and PTH-related peptide (PTHrP), a paracrine regulator of chondrocyte differentiation in growth plates, activate a common receptor (PTH/PTHrP receptor, PPR), which activates G s ␣ as well as other G-proteins (2-4). PTH stimulates bone formation and bone resorption, resulting in high bone remodeling (5).Different bones are formed by one of two different mechanisms, either intramembranous or endochondral ossification. Intramembranous ossification, which leads to formation of many of the flat bones, occurs when pluripotent mesenchymal cells directly enter an osteoblast lineage and differentiate into osteoblastic cells. Long bones develop by endochondral ossification in which a cartilage template is formed, and chondrocytes undergo hypertrophic differentiation and are then replaced by osteoblasts that form the primary spongiosa, which eventually forms the trabecular bone. Simultaneously, perichondrial cells surrounding the hypertrophic chondrocytes differentia...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Deficiency of the G-protein α-Subunit Gsα in Osteoblasts Leads to Differential Effects on Trabecular and Cortical Bone

Sakamoto¹,

Chen²,

Nakamura

et al. 2005

Journal of Biological Chemistry

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“…The gp130-/-mice had shortened limbs, as also observed in PTHrP-/-and PTH/PTHrP receptor-/-mice (Lanske et al, 1999), suggesting impairment not only in osteoblast differentiation but also in chondrocyte differentiation. As in other skeletal elements, Meckel's cartilage formation is initiated by condensation of prechondrogenic cells, which differentiate into chondrocytes and give rise to characteristic rod-shaped cartilage.…”

Section: Introductionsupporting

confidence: 61%

gp130 is important for the normal morphogenesis of Meckel's cartilage and subsequent mandibular development

Choi

Kim²,

Park³

et al. 2007

Exp Mol Med

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gp130-mediated signaling is involved in both chondrogenesis and osteogenesis, but its direct role in the formation of embryonic Meckel's cartilage and associated mandibular development has not yet been elucidated. In this study, we examined the influence of gp130 ablation on the developing mandibular Meckel's cartilage by evaluating the morphological and histological changes as well as the gene expression patterns in developing embryonic gp130-/-mice. The ablation of the gp130 gene showed no change in region-specific collagen mRNA expression except for a slight delay in its expression but caused shortened embryonic Meckel's cartilage, delayed hypertrophic chondrocyte maturation and subsequent bony replacement with characteristic bending of the intramandibular Meckel's cartilage. The bending of Meckel's cartilage led to a narrow mandibular arch at the rostral area with poor cortical plate formation. These findings indicate that gp130-mediated signaling is important for the normal morphogenesis of Meckel's cartilage and subsequent mandibular development.

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“…PTH-rP is expressed in 90% of primary prostate and lung spindle cell carcinomas and 50% of primary breast cancers (26 -29). It is highly expressed in fetal tissues, where it is involved in bone tissue differentiation (28). Low levels of PTH-rP have been sporadically detected in keratinocytes, uterus, and mammary glands during lactation (29).…”

mentioning

confidence: 99%

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

Francini¹,

Scardino

Kosmatopoulos

et al. 2002

The Journal of Immunology

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Parathyroid hormone-related protein (PTH-rP), a protein produced by prostate carcinoma and other epithelial cancers, is a key agent in the development of bone metastases. We investigated whether the protein follows the self-tolerance paradigm or can be used as a target Ag for anticancer immunotherapy by investigating the immunogenicity of two HLA-A(*)02.01-binding PTH-rP-derived peptides (PTR-2 and -4) with different affinity qualities. PTH-rP peptide-specific CTL lines were generated from the PBMC of two HLA-A(*)02.01+ healthy individuals, stimulated in vitro with PTH-rP peptide-loaded autologous dendritic cells and IL-2. The peptide-specific CTLs were able to kill PTH-rP+HLA-A(*)02.01+ breast and prostate carcinoma cell lines. The two peptides were also able to elicit a strong antitumor PTH-rP-specific CTL response in HLA-A(*)02.01 (HHD) transgenic mice. The vaccinated mice did not show any sign of side effects due to cell-mediated autoimmunity or toxicity. In this study we describe two immunogenic and toxic-free PTH-rP peptides as valid candidates for the design of peptide-based vaccination strategies against prostate cancer and bone metastases from the most common epithelial malignancies.

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Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

Cited by 223 publications

References 36 publications

Deficiency of the G-protein α-Subunit Gsα in Osteoblasts Leads to Differential Effects on Trabecular and Cortical Bone

Deficiency of the G-protein α-Subunit Gsα in Osteoblasts Leads to Differential Effects on Trabecular and Cortical Bone

gp130 is important for the normal morphogenesis of Meckel's cartilage and subsequent mandibular development

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

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