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

Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94121

Address all correspondence and requests for reprints to: Dr. Dolores Shoback, Endocrine Research Unit, 111N, San Francisco Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121. E-mail: dolores.shoback{at}ucsf.edu.

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-B 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.

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