Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism

Abstract

Parathyroid hormone (PTH)-related peptide (PTHrP) controls the pace of pre- and post-natal growth plate development by activating the PTH1R in chondrocytes, while PTH maintains mineral and skeletal homeostasis by modulating calciotropic activities in kidneys, gut, and bone. The extracellular calcium-sensing receptor (CaSR) is a member of family C G protein-coupled receptor, which regulates mineral and skeletal homeostasis by controlling PTH secretion in parathyroid glands and Ca2+ excretion in kidneys. Recent studies showed the expression of CaSR in chondrocytes, osteoblasts, and osteoclasts and confirmed its non-redundant roles in modulating the recruitment, proliferation, survival, and differentiation of the cells. This review emphasizes the actions of CaSR and PTH1R signaling responses in cartilage and bone and discusses how these two signaling cascades interact to control growth plate development and maintain skeletal metabolism in physiological and pathological conditions. Lastly, novel therapeutic regimens that exploit interrelationship between the CaSR and PTH1R are proposed to produce more robust osteoanabolism.

A Convenient In Vivo Model Using Small Interfering RNA Silencing to Rapidly Assess Skeletal Gene Function

“…In this proof-of-principle study, we used IGF-1 and rhPTH (1–34), two common bone anabolic agents that increase mesenchymal stem cell proliferation and osteoblast differentiation and result in enhanced bone formation primarily through their cognate receptors, IGF-1R and PTH1R [16,17]. In the current study, we developed a unique delivery approach by which siRNA and dendrimer nanoparticles could be delivered directly and locally to the target tissue.…”

“…In the present study, we used insulin-like growth factor-1 (IGF-1) and recombinant human parathyroid hormone (1–34) (rhPTH (1–34)), two common bone anabolic agents that increase mesenchymal stem cell proliferation and osteoblast differentiation and result in enhanced bone formation primarily by acting through their cognate receptors, insulin-like growth factor-1 receptor (IGF-1R) and parathyroid hormone 1 receptor (PTH1R) [16,17]. We hypothesized that silencing these receptors via intraosseous injection of small interfering RNA (siRNA) would block the expression of the corresponding genes, thus influencing bone remodeling and decreasing BMD, MARs and mechanical stress.…”

The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases

“…Their failure due to on-target effects on bone is because administering calcilytics is equivalent to ablating the CaSR and blocking the CaSR in bone cells has been shown to influence bone turnover (93-95). There have been many studies to show the essential role of the CaSR in osteoblast differentiation, survival, and proliferation (96). In osteoclasts, calcilytics have a different pharmacological profile, as compared to parathyroid cells, which can be due to decreasing pH in the resorption pits which makes the CaSR less responsive (96)(97)(98).…”

The Calcium-Sensing Receptor and the Parathyroid: Past, Present, Future

“…Recently developed mouse models, however, suggest that this is so (Chang et al, 2008; Richard et al, 2010; reviews: Goltzman and Hendy, 2015; Santa Maria et al, 2016). An authoritative database of CaSR mutations and their links to human disease is maintained at: http://www.casrdb.mcgill.ca/.…”