The importance of the vascular supply for bone is well-known to orthopaedists but is still rather overlooked within the wider field of skeletal research. Blood supplies oxygen, nutrients and regulatory factors to tissues, as well as removing metabolic waste products such as carbon dioxide and acid. Bone receives up to about 10% of cardiac output, and this blood supply permits a much higher degree of cellularity, remodelling and repair than is possible in cartilage, which is avascular. The blood supply to bone is delivered to the endosteal cavity by nutrient arteries, then flows through marrow sinusoids before exiting via numerous small vessels that ramify through the cortex. The marrow cavity affords a range of vascular niches that are thought to regulate the growth and differentiation of hematopoietic and stromal cells, in part via gradients of oxygen tension. The quality of vascular supply to bone tends to decline with age and may be compromised in common pathological settings, including diabetes, anaemias, chronic airway diseases and immobility, as well as by tumours. Reductions in vascular supply are associated with bone loss. This may be due in part to the direct effects of hypoxia, which blocks osteoblast function and bone formation but causes reciprocal increases in osteoclastogenesis and bone resorption. Common regulatory factors such as parathyroid hormone or nitrates, both of which are potent vasodilators, might exert their osteogenic effects on bone via the vasculature. These observations suggest that the bone vasculature will be a fruitful area for future research.

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The Key Role of the Blood Supply to Bone.

Cardiovascular cells (cardiomyocytes and smooth muscle cells) are target cells for parathyroid hormone (PTH) and the structurally related peptide parathyroid hormone-related peptide (PTH-rP). PTH activates protein kinase C (PKC) of cardiomyocytes via a PKC activating domain previously identified on chondrocytes. Activation of PKC leads to hypertrophic growth and re-expression of fetal type proteins in cardiomyocytes. This hypertrophic effect of PTH might contribute to left ventricular hypertrophy in hemodialysis patients with secondary hyperparathyroidism. PTH-rP is expressed in cardiovascular cells (endothelial cells and smooth muscle cells). It does not mimic the above described actions of PTH but exerts effects of its own on cardiomyocytes. These effects involve activation of protein kinase A, via a N-terminal domain distinct from that identified on PTH, and activation of PKC, via a C-terminally located domain distinct from that found on PTH. On smooth muscle cells PTH and PTH-rP reduce the influence of extracellular calcium, through cAMP-dependent mechanisms. These inhibitory effects on voltage-dependent L-type calcium channels of smooth muscle cells cause vasorelaxation. Present studies concerning cardiovascular actions of either PTH and PTH-rP suggest that increased plasma levels of PTH and PTH-rP influence cardiomyocyte and smooth muscle cell physiology. It can be assumed that PTH-rP acts as a paracrine or autocrine modulator in heart and vessels.

Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide

Cyclic AMP and mechanisms of vasodilation.

Within recent years a variety of agents have been employed for the symptomatic and prophylactic treatment of the migraine syndrome. The responses to two such agents, ergot derivatives and methysergide, have often been so striking as to have achieved the stature of diagnostic criteria. Despite this fact, a number of migraine sufferers remain without effective therapy because either they are not benefited by these drugs or they cannot risk or tolerate the side effects produced by them. Recently, Rabkin et aL,l Wykes,z and Bekes et a13 independently noted seemingly fortuitous headache improvement in three patients with migraine treated for cardiovascular disease with propranolol, a beta-adrenergic receptor blocker. These observations coupled with our experimental results of propranolol's effects on cerebral blood flow and metabolism* prompted a controlled study on the efficacy of this substance as a modifier of the migraine syndrome.

https://n.neurology.org/content/neurology/22/4/366.full.pdf

The treatment of migraine with propranolol

Twenty-five years ago a "new" protein was identified from cancers that caused hypercalcemia. It was credited for its ability to mimic parathyroid hormone (PTH), 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, and its 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. © 2012 American Society for Bone and Mineral Research.

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G.A. Charbon

Papers

A rapid and selective vasodilator effect of parathyroid hormone

The effects of β-receptor agonists and antagonists on regional blood flow