Constitutive Activity of the Osteoblast Ca2+-Sensing Receptor Promotes Loss of Cancellous Bone

Abstract

Changes in extracellular [Ca2+] modulate the function of bone cells in vitro via the extracellular Ca2+-sensing receptor (CaR). Within bone microenvironments, resorption increases extracellular [Ca2+] locally. To determine whether enhanced CaR signaling could modulate remodeling and thereby bone mass in vivo, we generated transgenic mice with a constitutively active mutant CaR (Act-CaR) targeted to their mature osteoblasts by the 3.5 kb osteocalcin promoter. Longitudinal microcomputed tomography of cancellous bone revealed reduced bone volume and density, accompanied by a diminished trabecular network, in the Act-CaR mice. The bone loss was secondary to an increased number and activity of osteoclasts, demonstrated by histomorphometry of secondary spongiosa. Histomorphometry, conversely, indicates that bone formation rates were unchanged in the transgenic mice. Constitutive signaling of the CaR in mature osteoblasts resulted in increased expression of RANK-L (receptor activator of nuclear factor-kappaB ligand), the major stimulator of osteoclast differentiation and activation, which is the likely underlying mechanism for the bone loss. The phenotype of Act-CaR mice is not attributable to systemic changes in serum [Ca2+] or PTH levels. We provide the first in vivo evidence that increased signaling by the CaR in mature osteoblasts can enhance bone resorption and further propose that fluctuations in the [Ca2+] within the bone microenvironment may modulate remodeling via the CaR.

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

“…In addition, in studies in vivo, it has been reported that transgenic mice expressing a constitutively active mutant Casr in mature osteoblasts display increased expression of RANKL, an increased number and activity of osteoclasts, and reduced bone volume. (11) Reduced RANKL signaling in the Casr À/À 1a(OH)ase À/À mice therefore may represent an additional mechanism of reduced osteoclastogenesis in the absence of the CaSR. Consequently, both hypocalcemia in the 1a(OH)ase À/À mice and CaSR deficiency in the double mutants appear to lead to inappropriately low or reduced calcium signaling in bone, resulting in diminished osteoclastogenesis, an impediment that cannot be overcome by high circulating PTH.…”

“…(10) By in situ hybridization, Casr transcripts have been found mainly in hypertrophic chondrocytes of the epiphyseal growth plate, in osteoblasts, in osteocytes, and in bone marrow cells but rarely in mature osteoclasts. Recent in vivo studies have shown that transgenic mice with a constitutively active mutant CaSR targeted to mature osteoblasts demonstrated enhanced bone resorption, (11) whereas mice with osteoblast-specific deletion exhibited severely undermineralized skeletons. (12) Mice with chondrocyte-specific deletion of Casr displayed delayed growth plate development.…”

The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice

“…By in situ hybridization, CaSR transcripts have been found mainly in osteoblasts, osteocytes, and bone marrow cells but rarely in mature osteoclasts. In vivo studies have shown that transgenic mice, with a constitutively active mutant CaSR targeted to mature osteoblasts, demonstrate enhanced bone resorption due to an associated increase in RANKL (10). Although bone formation rates were unchanged in this model, bone mineral density (BMD) and bone volume decreased.…”

Influência da remodelação óssea na transferência de cálcio e fósforo durante hemodiálise em pacientes com doença renal crônica

“…Recentemente foi demonstrada a presença de receptores sensores de Ca (CaSR) em células ósseas e estes poderiam participar na regulação do Ca sérico. Kameda e colaboradores, assim como Mentaverri e colaboradores mostraram a presença destes receptores em pré-osteoclastos e osteoclastos (41,42) e Dvorak e colaboradores demonstraram a presença em osteoblastos (43). Além disto, Huan e colaboradores avaliaram a recuperação de hipocalcemia aguda induzida em ratos tireoparatireoidectomizados tratados ou não com calcimimético.…”

“…Para analisar a participação do PTH na transferência de Ca e na remoção de P, os pacientes foram divididos em dois grupos de acordo com os níveis de PTH, ou seja PTH 43 ≤ 300 pg/ml e PTH > 300 pg/ml (84). O grupo de pacientes com níveis de PTH ≤ 300 pg/ml foi considerado apresentar remodelação óssea normal ou baixa, enquanto o grupo com PTH > 300 pg/ml alta remodelação.…”