The Role of the Calcium-Sensing Receptor in Bone Biology and Pathophysiology

Abstract

Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca2+). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We review the relevant mouse models and discuss the importance of CaR in chondrogenesis and osteogenesis. We present the evidence for a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations. Additionally, we review emerging research on the importance of the CaR to the regulation of serum calcium homeostasis independent of PTH, the role of the CaR in the hematopoietic stem cell niche with implications for bone marrow transplant, and early evidence that implies a role for the CaR as a factor in skeletal metastasis from breast and prostate cancer. We conclude with a discussion of drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), and the consequences for bone physiology and pathology.

Calcium Sensing Receptor Modulation for Cancer Therapy

“…CaSR activation increased attachment of cells to extracellular matrix (Sanders et al, 2001). Increased adherence was reduced by the addition of pertussis toxin, a CaSR antagonist (Theman and Collins, 2009). CaSR signals, in part, through MAP kinase to stimulate PTHrP (Chattopadhyay, 2006).…”

“…Finally, in a series of elegant experiments using CaSR-/-mice, Adams et al demonstrated that it is the mineral content of the niche dictates HSC localization via the CaSR (Adams et al, 2006). These mechanisms by which the CaR dictates preferential localization of HSCs in the bone marrow endosteal region may provide additional insights for the fundamental interrelationship between the stem cell niche and stem cell fate (Theman and Collins, 2009). …”

“…CaSR-/-HSCs successfully localized to the endosteal niche using a SDF-1 gradient, though they could not lodge, suggesting that CaSR functions downstream of SDF-1 in HSC homing to bone. Blocking of SDF-1 signaling reduced metastasis (Theman and Collins, 2009). …”

Vitamin D and the Calcium-Sensing Receptor

“…As noted earlier, some [105,120,121] but not all [122] studies demonstrated the presence of the CaSR in bone, primary cultured osteoblasts and osteoblastic cell lines (for review, see [106]). In osteoblastic cells expressing the CaSR, high Ca 2þ o , acting at least in part via the CaSR, exerts effects that would be expected to promote bone formation.…”

“…While some studies found clear evidence for the receptor's presence in cartilage or chondrocytic cell lines [104,105] and/or bone [105] as well as in osteoblastic cell lines, and/or osteoclasts and related cell lines, others did not (for review, see [106]). The following discussion summarizes the current state of this field and compares and contrasts the relative roles of the CaSR and VDR in cartilage and bone cells.…”