Comprehensive Physiology Wiley Online Library

Bone Marrow Microvasculature

Full Article on Wiley Online Library



Abstract

The skeleton is highly vascularized due to the various roles blood vessels play in the homeostasis of bone and marrow. For example, blood vessels provide nutrients, remove metabolic by‐products, deliver systemic hormones, and circulate precursor cells to bone and marrow. In addition to these roles, bone blood vessels participate in a variety of other functions. This article provides an overview of the afferent, exchange and efferent vessels in bone and marrow and presents the morphological layout of these blood vessels regarding blood flow dynamics. In addition, this article discusses how bone blood vessels participate in bone development, maintenance, and repair. Further, mechanical loading‐induced bone adaptation is presented regarding interstitial fluid flow and pressure, as regulated by the vascular system. The role of the sympathetic nervous system is discussed in relation to blood vessels and bone. Finally, vascular participation in bone accrual with intermittent parathyroid hormone administration, a medication prescribed to combat age‐related bone loss, is described and age‐ and disease‐related impairments in blood vessels are discussed in relation to bone and marrow dysfunction. © 2020 American Physiological Society. Compr Physiol 10:1009‐1046, 2020.

Figure 1. Figure 1. A 3D microCT reconstruction of a scanned (10 μm) rat femur. The epiphyses, metaphyses, and diaphysis have been labeled. The higher magnification inset denotes the femoral head, the lesser trochanter and principle nutrient foramen.
Figure 2. Figure 2. A 3D microCT reconstruction of a scanned (10 μm) rat femur. A frontal section of the distal femur is being displayed. The reconstruction illustrates the interior trabecular bone, which is distinguishable from the outer covering of cortical bone. The growth plate is also observable. Marrow, which not visible in the 3D reconstruction, lies between the trabeculae.
Figure 3. Figure 3. A 3D microCT reconstruction of a scanned (10 μm) rat femur. A frontal section is being displayed. The reconstruction denotes the periosteal surface, the endosteal surface, the diaphyseal cortex, and the marrow cavity.
Figure 4. Figure 4. An illustration of an osteon of cortical bone. The vascular supply is observed in the Haversian and Volkmann's canal. Volkmann's canals run perpendicular to the long axis of the bone and connect with the Haversian canals. In Haversian and Volkmann's canals, sympathetic and sensory nerve fibers (not depicted) either coil around or run linear to the blood vessel. Osteocytes, housed in lacunae, can be observed surrounding and radiating away from the Haversian canal. Osteocytes extend dendritic processes into the interconnected canaliculi. The schematic is not drawn to scale.
Figure 5. Figure 5. The cell‐to‐cell communications among osteocytes, osteoblasts, and osteoclasts. (a) Apoptosis of osteocytes elicits the production of NFκB ligand (RANKL) to ultimately stimulate osteoclastogenesis. (b) Bone marrow stromal cells, osteoblasts/osteoblast lineage cells and osteocytes release RANKL to stimulate fusion and osteoclastogenesis. (c) Bone marrow stromal cells, osteoblasts/osteoblast lineage cells, and osteocytes secrete monocyte‐colony stimulating factor (M‐CSF), causing osteoclast precursors to proliferate and commit to the osteoclast lineage. (d) Bone marrow stromal cells, osteoblasts, and osteocytes release osteoprotegerin (OPG); that is, a decoy receptor for RANKL. The binding of OPG to the receptor, RANK, on pre‐osteoclasts inhibits osteoclastogenesis. (e) Osteoblasts release Dickkopf‐1 (Dkk‐1, a Wnt antagonist), attenuating or preventing continued bone formation. (f) Osteocytes also release Dkk‐1, inhibiting osteoblast activity. (g) Osteocytes secret sclerostin and disrupt Wnt/β‐catenin signaling, diminishing bone formation by osteoblasts.
Figure 6. Figure 6. Coupling factors and osteotransmitters associated with cell‐to‐cell communication. During bone remodeling, osteoclast and osteoblast activity are coupled. During bone resorption matrix‐bound factors [e.g., insulin‐like growth factor‐1 (IGF‐1) and tumor growth factor‐β (TGF‐β)] are released and can influence osteoblast activity. Thus, bone resorption leads to bone formation. In addition, coupling factors secreted directly by osteoclasts contribute more so to coupling than matrix‐secreted factors. These factors include Sema4D, cardiotrophin‐1, Wnt10b, BMP 6, sphingosine‐1 phosphate, and collagen triple helix repeat containing 1 (CTHRC1).
Figure 7. Figure 7. The vascular pattern of long bones. This illustration is a simplified depiction of the vascular density of the skeleton and is not drawn to scale. The afferent (nutrient arteries, arteries, and arterioles), exchange (capillaries, sinusoids, and sinusoidal lobules), and efferent (nutrient veins, veins, and venules) blood vessels are depicted in red, purple and blue, respectively. Epiphyseal and metaphyseal blood vessels service the epiphyses and metaphyses of long bones. The principal nutrient artery and vein service the marrow cavity and inner 2/3rd of the diaphyseal cortex. The periosteal arteries and veins service the outer 1/3rd of the diaphyseal cortex. The vascular supply differs with advancing age, whereby the periosteal arteries provide most of the blood flow. Within cortical bone, blood vessels are contained within Haversian, Volkmann's and transcortical canals. Note that nutrient vessels also supply the distal end of the femur but are not depicted in the schematic.
Figure 8. Figure 8. (A) The basic multicellular unit of cortical bone and (B) the bone remodeling compartment of trabecular bone. The vascular supply is denoted in panels A and B and represents an arteriole (red), capillary (purple) and venule (blue). Remodeling at both trabecular and cortical surfaces begins with bone resorption by osteoclasts. Osteoclasts dig into cortical bone and excavate the surface of trabecular bone. Once resorption has finished, osteoblasts lay down osteoid seams that eventually mineralize into bone. The capillary associated with basic multicellular units and bone remodeling compartments exchange nutrients and precursor cells at the remodeling site. Typically, the vascular supply in similar schematics depicts just the capillary. However, arterioles deliver nutrients and precursor cells and venules collect metabolic by‐products from capillaries. Therefore, it is important to recognize the ingress and egress vessels associated with the exchange network. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. The schematics are not drawn to scale.
Figure 9. Figure 9. The spatial location of marrow capillaries in relation to bone remodeling sites (i.e., osteoid seams and/or eroded surfaces) and quiescent trabecular surfaces 214,302. Note, capillaries are physically closer to the bone‐forming sites in comparison to the quiescent surfaces 214,302. In addition, capillaries next to remodeling sites run tangential to the bone surfaces as opposed to capillaries next to quiescent surfaces, which run perpendicular to the bone surface 214. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. The schematics are not drawn to scale.
Figure 10. Figure 10. The associated figure and legend were originally published in 299. The schematic represents “a sequential scenario by which metabolic activity leads to enhanced vasodilation of the surrounding arterioles and arteries. The schematic represents the bone remodeling compartment with trabecular bone containing osteocytes and the neighboring marrow occupied by osteoclasts, osteoblasts, bone lining cells, and the vascular network (i.e., arteriole, capillary, and venule). Panel A serves to orient the reader to the various cells and structures within this schematic. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. Panel B depicts osteoclasts actively resorbing bone (a). During enhanced metabolism, the osteoclasts release factors (e.g., carbon dioxide (CO2), hydrogen ion (H+), phosphate (PO4), ADP, lactate) that diffuse to the arteriole and initiate metabolic vasodilation (b). The metabolic vasodilation of the arteriole causes ascending vasodilation of the feed and conduit arteries upstream (not depicted). This process is called Conducted Vasodilation and ensures a rise in blood flow to the surrounding tissue undergoing metabolism. Panel C illustrates how vasodilation and the subsequent rise in blood flow (c) augments filtration and pressure from the capillary (d) into the bone interstitial space (e). The increased bone interstitial pressure and fluid flow generate shear stress on bone cells (Panel D, f). Shear‐mediated release of PGE2 and NO from osteoblasts (g) serves to enhanced osteoblast activity and reduced osteoclast activity, slowing down bone degradation and ramping up bone formation. In addition, enhanced blood flow as a result of conducted vasodilation augments shear stress on vascular endothelial cells (Panel E, h). As a result, vascular endothelial cells release factors [e.g., NO, PGE2, prostacyclin (PGI2)] that diffuse into the bone interstitial space to stimulate osteoblast activity and inhibit osteoclast activity (i). The theories of vascular contribution to enhanced bone formation were previously put forth by the laboratory of Michael Delp 88. Note that these processes do not have to begin with osteoclast activity. For example, circulating factors that induce vasodilation in the bone vascular network will serve to commence similar processes.”
Figure 11. Figure 11. The associated figure and legend were originally published in 299. The schematic represents “centrifugal (young) and centripetal (old) blood flow supply in long bones 68. Centrifugal blood flow indicates that blood enters the long bone through the principal nutrient artery (PNA), flows into the middle of the marrow space, radiates to the endosteal network and exits primarily via the periosteal venular network (PVN). Blood is also capable of exiting via the principal nutrient vein (PNV). Progressive ossification of bone marrow blood vessels may contribute to and precipitate the transition of the blood supply from centrifugal in youth to centripetal in old age. By reducing or eliminating the patency of the bone marrow vasculature (i.e., the black X), the blood supply must predominately enter the long bone via the periosteal arterial network (PAN). Centripetal blood supply represents an abnormal blood flow pattern 65 and has been previously represented as a schematic 366.”


Figure 1. A 3D microCT reconstruction of a scanned (10 μm) rat femur. The epiphyses, metaphyses, and diaphysis have been labeled. The higher magnification inset denotes the femoral head, the lesser trochanter and principle nutrient foramen.


Figure 2. A 3D microCT reconstruction of a scanned (10 μm) rat femur. A frontal section of the distal femur is being displayed. The reconstruction illustrates the interior trabecular bone, which is distinguishable from the outer covering of cortical bone. The growth plate is also observable. Marrow, which not visible in the 3D reconstruction, lies between the trabeculae.


Figure 3. A 3D microCT reconstruction of a scanned (10 μm) rat femur. A frontal section is being displayed. The reconstruction denotes the periosteal surface, the endosteal surface, the diaphyseal cortex, and the marrow cavity.


Figure 4. An illustration of an osteon of cortical bone. The vascular supply is observed in the Haversian and Volkmann's canal. Volkmann's canals run perpendicular to the long axis of the bone and connect with the Haversian canals. In Haversian and Volkmann's canals, sympathetic and sensory nerve fibers (not depicted) either coil around or run linear to the blood vessel. Osteocytes, housed in lacunae, can be observed surrounding and radiating away from the Haversian canal. Osteocytes extend dendritic processes into the interconnected canaliculi. The schematic is not drawn to scale.


Figure 5. The cell‐to‐cell communications among osteocytes, osteoblasts, and osteoclasts. (a) Apoptosis of osteocytes elicits the production of NFκB ligand (RANKL) to ultimately stimulate osteoclastogenesis. (b) Bone marrow stromal cells, osteoblasts/osteoblast lineage cells and osteocytes release RANKL to stimulate fusion and osteoclastogenesis. (c) Bone marrow stromal cells, osteoblasts/osteoblast lineage cells, and osteocytes secrete monocyte‐colony stimulating factor (M‐CSF), causing osteoclast precursors to proliferate and commit to the osteoclast lineage. (d) Bone marrow stromal cells, osteoblasts, and osteocytes release osteoprotegerin (OPG); that is, a decoy receptor for RANKL. The binding of OPG to the receptor, RANK, on pre‐osteoclasts inhibits osteoclastogenesis. (e) Osteoblasts release Dickkopf‐1 (Dkk‐1, a Wnt antagonist), attenuating or preventing continued bone formation. (f) Osteocytes also release Dkk‐1, inhibiting osteoblast activity. (g) Osteocytes secret sclerostin and disrupt Wnt/β‐catenin signaling, diminishing bone formation by osteoblasts.


Figure 6. Coupling factors and osteotransmitters associated with cell‐to‐cell communication. During bone remodeling, osteoclast and osteoblast activity are coupled. During bone resorption matrix‐bound factors [e.g., insulin‐like growth factor‐1 (IGF‐1) and tumor growth factor‐β (TGF‐β)] are released and can influence osteoblast activity. Thus, bone resorption leads to bone formation. In addition, coupling factors secreted directly by osteoclasts contribute more so to coupling than matrix‐secreted factors. These factors include Sema4D, cardiotrophin‐1, Wnt10b, BMP 6, sphingosine‐1 phosphate, and collagen triple helix repeat containing 1 (CTHRC1).


Figure 7. The vascular pattern of long bones. This illustration is a simplified depiction of the vascular density of the skeleton and is not drawn to scale. The afferent (nutrient arteries, arteries, and arterioles), exchange (capillaries, sinusoids, and sinusoidal lobules), and efferent (nutrient veins, veins, and venules) blood vessels are depicted in red, purple and blue, respectively. Epiphyseal and metaphyseal blood vessels service the epiphyses and metaphyses of long bones. The principal nutrient artery and vein service the marrow cavity and inner 2/3rd of the diaphyseal cortex. The periosteal arteries and veins service the outer 1/3rd of the diaphyseal cortex. The vascular supply differs with advancing age, whereby the periosteal arteries provide most of the blood flow. Within cortical bone, blood vessels are contained within Haversian, Volkmann's and transcortical canals. Note that nutrient vessels also supply the distal end of the femur but are not depicted in the schematic.


Figure 8. (A) The basic multicellular unit of cortical bone and (B) the bone remodeling compartment of trabecular bone. The vascular supply is denoted in panels A and B and represents an arteriole (red), capillary (purple) and venule (blue). Remodeling at both trabecular and cortical surfaces begins with bone resorption by osteoclasts. Osteoclasts dig into cortical bone and excavate the surface of trabecular bone. Once resorption has finished, osteoblasts lay down osteoid seams that eventually mineralize into bone. The capillary associated with basic multicellular units and bone remodeling compartments exchange nutrients and precursor cells at the remodeling site. Typically, the vascular supply in similar schematics depicts just the capillary. However, arterioles deliver nutrients and precursor cells and venules collect metabolic by‐products from capillaries. Therefore, it is important to recognize the ingress and egress vessels associated with the exchange network. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. The schematics are not drawn to scale.


Figure 9. The spatial location of marrow capillaries in relation to bone remodeling sites (i.e., osteoid seams and/or eroded surfaces) and quiescent trabecular surfaces 214,302. Note, capillaries are physically closer to the bone‐forming sites in comparison to the quiescent surfaces 214,302. In addition, capillaries next to remodeling sites run tangential to the bone surfaces as opposed to capillaries next to quiescent surfaces, which run perpendicular to the bone surface 214. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. The schematics are not drawn to scale.


Figure 10. The associated figure and legend were originally published in 299. The schematic represents “a sequential scenario by which metabolic activity leads to enhanced vasodilation of the surrounding arterioles and arteries. The schematic represents the bone remodeling compartment with trabecular bone containing osteocytes and the neighboring marrow occupied by osteoclasts, osteoblasts, bone lining cells, and the vascular network (i.e., arteriole, capillary, and venule). Panel A serves to orient the reader to the various cells and structures within this schematic. Vascular smooth muscle cells were omitted from the arteriole and venule for simplicity; thus, the cells being depicted are vascular endothelial cells. Panel B depicts osteoclasts actively resorbing bone (a). During enhanced metabolism, the osteoclasts release factors (e.g., carbon dioxide (CO2), hydrogen ion (H+), phosphate (PO4), ADP, lactate) that diffuse to the arteriole and initiate metabolic vasodilation (b). The metabolic vasodilation of the arteriole causes ascending vasodilation of the feed and conduit arteries upstream (not depicted). This process is called Conducted Vasodilation and ensures a rise in blood flow to the surrounding tissue undergoing metabolism. Panel C illustrates how vasodilation and the subsequent rise in blood flow (c) augments filtration and pressure from the capillary (d) into the bone interstitial space (e). The increased bone interstitial pressure and fluid flow generate shear stress on bone cells (Panel D, f). Shear‐mediated release of PGE2 and NO from osteoblasts (g) serves to enhanced osteoblast activity and reduced osteoclast activity, slowing down bone degradation and ramping up bone formation. In addition, enhanced blood flow as a result of conducted vasodilation augments shear stress on vascular endothelial cells (Panel E, h). As a result, vascular endothelial cells release factors [e.g., NO, PGE2, prostacyclin (PGI2)] that diffuse into the bone interstitial space to stimulate osteoblast activity and inhibit osteoclast activity (i). The theories of vascular contribution to enhanced bone formation were previously put forth by the laboratory of Michael Delp 88. Note that these processes do not have to begin with osteoclast activity. For example, circulating factors that induce vasodilation in the bone vascular network will serve to commence similar processes.”


Figure 11. The associated figure and legend were originally published in 299. The schematic represents “centrifugal (young) and centripetal (old) blood flow supply in long bones 68. Centrifugal blood flow indicates that blood enters the long bone through the principal nutrient artery (PNA), flows into the middle of the marrow space, radiates to the endosteal network and exits primarily via the periosteal venular network (PVN). Blood is also capable of exiting via the principal nutrient vein (PNV). Progressive ossification of bone marrow blood vessels may contribute to and precipitate the transition of the blood supply from centrifugal in youth to centripetal in old age. By reducing or eliminating the patency of the bone marrow vasculature (i.e., the black X), the blood supply must predominately enter the long bone via the periosteal arterial network (PAN). Centripetal blood supply represents an abnormal blood flow pattern 65 and has been previously represented as a schematic 366.”
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Rhonda D. Prisby. Bone Marrow Microvasculature. Compr Physiol null, 10: 1009-1046. doi: 10.1002/cphy.c190009