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.

Gene expression profile comparison of primary and pulmonary metastatic lesions in a dog with appendicular osteosarcoma and hypertrophic osteopathy

“…The most downregulated gene was PTHLH, which encodes a protein involved in the regulation of endochondral bone development, as well as epithelial-mesenchymal interactions during the formation of mammary glands and teeth (41)(42)(43). The overexpression of its receptor PTHR1 in OSA has been associated with increased invasion and proliferation and conversely, decreased mRNA expression of PTHR1 has been associated with inhibition of proliferation, migration, and invasion in human OSA cell lines (44,45). Patients with strong staining for PTHR1 in canine OSA tumors had reduced survival times compared to those with weak immunostaining intensity (45).…”

“…The overexpression of its receptor PTHR1 in OSA has been associated with increased invasion and proliferation and conversely, decreased mRNA expression of PTHR1 has been associated with inhibition of proliferation, migration, and invasion in human OSA cell lines (44,45). Patients with strong staining for PTHR1 in canine OSA tumors had reduced survival times compared to those with weak immunostaining intensity (45). Another downregulated gene was THBS1, a gene that encodes for the TSP1 protein, a glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.…”

BNTA alleviates inflammatory osteolysis by the SOD mediated anti-oxidation and anti-inflammation effect on inhibiting osteoclastogenesis

“…Overactivated osteoclastogenesis and excessive bone resorption during the bone remodeling process occur in a variety of inflammatory osteolytic bone diseases, such as osteoarthritis, inflammatory aseptic prosthetic loosening, periprosthetic infection, and osteomyelitis ( Roux and Richette, 2012 ; Gallo et al, 2013 ; Loi et al, 2016 ). Current clinically available therapeutic agents for inflammatory osteolysis like estrogen, bisphosphonates, and parathyroid hormone are effective, but still have some limitations and side effects including increased cancer risks, aseptic jaw osteonecrosis, and atypical femur fracture ( Clemons and Goss, 2001 ; Woo et al, 2006 ; Shane et al, 2014 ; Nikitovic et al, 2016 ; Lobo, 2017 ; Al-Khan et al, 2021 ). Therefore, the pursuit of novel and effective drug candidates that can safely treat osteolytic bone disorders is always required.…”

“…Over the past few decades, there have been some advances in the treatment of inflammatory osteolytic bone diseases, but some limitations remain. Estrogen is mainly used to treat osteoporosis in postmenopausal women, but it carries a risk of breast cancer ( Clemons and Goss, 2001 ; Lobo, 2017 ); bisphosphonates are used to inhibit osteoclastic bone resorption, but they are increasingly reported to be associated with the occurrence of aseptic necrosis of the mandible and local fractures ( Woo et al, 2006 ; Shane et al, 2014 ); parathyroid hormone increases bone formation by promoting osteoblast activity, but it cannot be taken orally and cannot be used for a long time because it risks causing bone tumors ( Nikitovic et al, 2016 ; Al-Khan et al, 2021 ). Therefore, there is still a great need to develop more effective and safe anti-osteolytic drugs.…”

A Systematic Review of the Expression, Signalling and Function of P2 Receptors in Primary Bone Cancer

“…In OS cell lines the studies showed interactions with reactive oxygen species and systemic factors such as PTH in mediating Ca 2+ signalling. Previous investigations studying PTH in OS have shown that it is upregulated and correlates with poor prognosis, tumorigenesis, chemoresistance and metastasis [73] and therefore the relationship between PTH and P2 signalling could provide a novel target for treatment. Further to this, downstream of Ca 2+ signalling, c-fos induction has been reported in response to both P2RY1 [52] and P2RY2 [50], in nonmalignant osteoblasts, upregulation of c-fos has been shown to regulate proliferation and differentiation during development [74] whilst c-fos overexpression in bone is known to cause transgenic mice to develop OS [75].…”