Twenty-five years of PTHrP progress: From cancer hormone to multifunctional cytokine

Abstract

Twenty-five years ago a ‘new’ protein was identified from cancers that caused hypercalcemia. It was credited for its ability to mimic parathyroid hormone, and hence was termed parathyroid hormone-related protein (PTHrP). Today it is recognized for its widespread distribution, its endocrine, paracrine, and intracrine modes of action driving numerous physiologic and pathologic conditions with a central role in organogenesis. The multiple biological activities within a complex molecule with paracrine modulation of adjacent target cells present boundless possibilities. The protein structure of PTHrP has been traced, dissected and deleted comprehensively and conditionally, yet numerous questions lurk in its past that will carry into the future. Issues of the variable segments of the protein including the enigmatic nuclear localization sequence are only recently being clarified. Aspects of PTHrP production and action in the menacing condition of cancer are emerging as dichotomies that may represent intended temporal actions of PTHrP. Relative to PTH, the hormone regulating calcium homeostasis, PTHrP ‘controls the show’ locally at the PTH/PTHrP receptor throughout the body. Great strides have been made in our understanding of PTHrP actions, yet years of exciting investigation and discovery are imminent.

Ephrin‐B stimulation of calvarial bone formation

“…The advantage of the novel ephrin mechanism is that it prevents resorption from competing with synthesis at the same physical location on remodeling bone surfaces. These authors' hypothesis is supported by molecular profiling studies by Allan et al that found ephrin-B2 expression was increased in OBs and osteoblastic cell lines in response to treatment with parathyroid hormone (PTH) or parathyroid hormone-related peptide (PTHrP), both of which are important regulators of bone homeostasis (Silva et al, 2011;McCauley and Martin, 2012).…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…The factor, which had long been suspected of being a PTH-like entity, was indeed found to be a polypeptide that not only induced the same effects on bone and kidney cells as PTH did, but shared amino acid sequence homology with PTH, at least within the N-terminal region that was known to be critical for activity ( Fig. 2) (Suva et al, 1987;Nissenson et al, 1988;McCauley and Martin, 2012). A true biologic role for PTHrP was then established in 1994 by the gene "knockout" approach, because the PTHrP-null mice died at birth with developmental abnormalities, particularly affecting the skeleton (Karaplis et al, 1994).…”

“…PTHrP was thus found to be produced by cells at the peripheries of the developing bone template and to act in a paracrine fashion on the chondrocytes within the template to promote their proliferation and slow their terminal differentiation toward the hypertrophic state (Kronenberg, 2006). It is now clear that in addition to bone, PTHrP plays a role in the development of several other tissues, including the mammary glands (Wysolmerski et al, 1998) and teeth , and is widely expressed among various organ systems, suggesting a generally broad functional role as a paracrine-acting regulatory factor (Trivett et al, 2005;McCauley and Martin, 2012).…”

The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone–Related Peptide

“…(2,3) PTHrP is a polyhormone that can be translated and processed into several smaller bioactive forms. The N-terminal region of PTHrP, ie, PTHrP , mediates "classical" PTH-like effects.…”