Roles of Parathyroid Hormone-Related Protein (PTHrP) and Its Receptor (PTHR1) in Normal and Tumor Tissues: Focus on Their Roles in Osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary bone tumor and originates from bone forming mesenchymal cells and primarily affects children and adolescents. The 5-year survival rate for OS is 60 to 65%, with little improvement in prognosis during the last four decades. Studies have demonstrated the evolving roles of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation, bone remodeling, regulation of calcium transport from blood to milk, regulation of maternal calcium transport to the fetus and reabsorption of calcium in kidneys. These two molecules also play critical roles in the development, progression and metastasis of several tumors such as breast cancer, lung carcinoma, chondrosarcoma, squamous cell carcinoma, melanoma and OS. The protein expression of both PTHrP and PTHR1 have been demonstrated in OS, and their functions and proposed signaling pathways have been investigated yet their roles in OS have not been fully elucidated. This review aims to discuss the latest research with PTHrP and PTHR1 in OS tumorigenesis and possible mechanistic pathways. This review is dedicated to Professor Michael Day who died in May 2020 and was a very generous collaborator.

Keywords: canine; osteosarcoma; parathyroid hormone; parathyroid hormone related protein; prognostic factor.

Figure 1

The regulation of cartilage and bone formation. Diagrammatic representation of the network of signaling factors involved in cartilage and bone formation. Starting with the creation of mesenchymal condensations and their subsequent transition to differentiated cartilage and bone. The cells are represented as osteoblasts , pre-osteoblasts , chondroblasts , chondrocytes , osteoclasts , hypertrophic chondrocytes , adipocytes and myocytes . Reproduced with permission from reference (59).

Figure 2

The actions of PTH and PTHrP on new bone formation. If PTHrP and PTH are given intermittently to patients, they increase the formation of new bone but if either are given continuously, they increase resorption by stimulating osteoclasts to remodel bone . Both act via PTHR1 . Reproduced with permission from reference (59).

Figure 3

Roles of PTHrP on two of the OS subtypes. Subtypes of OS arise from pre-osteoblasts that accrue mutations (possibly in Rb or p53). PTHrP, PTHR1 and CREB activity are increased in osteoblastic OS influencing proliferation (99, 100) when compared to fibroblastic OS. Also, the intracrine PTHrP (iPTHrP) may contribute to this process.

Figure 4

Possible outcomes for dogs with osteosarcoma. Dogs with strong PTHR1 immunostaining tumors had shorter overall survival times compared to those with weak immunostaining. Overabundance of PTHR1 could activate neoplastic osteoblasts to detach via up-regulation of integrin adhesion molecules (αvβ3, β1, α2β1, α5β1, α6β1), resulting in pulmonary metastases. Other possible mechanisms which could explain the effects of PTHR1 expression including increased chemoresistance, increased tumor growth and decreased apoptosis. This might result in shorter survival time.