Blood vessels within bone marrow may progressively convert into bone with advancing age

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The early stage of cartilage canal formation. Perichondrial vascular network (PV) sends off hairpin loops (H) which form capillary glomeruli (G) at their ends; 13-week-fetus. Bar 100 gm

A researcher at The University of Texas at Arlington has found that blood vessels within bone marrow may progressively convert into bone with advancing age.

Examination of these vessels by Rhonda Prisby, associate professor of kinesiology in the College of Nursing and Health Innovation, led to the discovery of bone-like particles in the peripheral circulation.

Her findings have recently been published in the journal Microcirculation and suggest that ossified particles may contribute to diseases such as vascular calcification, heart attack, stroke and inadequate blood supply to the limbs.

“By examining seemingly unrelated images and linking the details of them together, I was able to posit the presence of bone-like particles in the blood,” Prisby said “In fact, some of the ossified particles are large enough to clog the smallest blood vessels in the vascular tree.”

Approximately 610,000 people die each year from a heart disease-related event, making it the leading cause of death for both men and women in the United States, according to the Centers for Disease Control and Prevention.

Vascular calcification is a common characteristic and risk factor for morbidity and mortality, Prisby said. These bone-like particles are potentially more dangerous because of their sharp edges.

“Some of the ossified particles have sharp tips and edges that could damage the lining of blood vessels,” she said. “This damage could initiate events leading to atherosclerosis (build-up of plaque), which can restrict blood flow over time.”

The discovery of these bone-like particles could help physicians detect and treat potentially life-threatening conditions.

“When looking for etiologies related to vascular calcification, heart attack and/or stroke, perhaps we should consider if and how ossified particles contribute to these diseases,” Prisby said. “My lab will examine these possibilities.”


The vascular system is important for bone and bone marrow. Immune cells are produced in the bone marrow [1] and blood vessels serve a role in hematopoietic stem cell niches [2]. In addition, capillaries are integral components of bone basic multicellular units and may coordinate the activities of osteoblasts and osteoclasts [34].

Further, alterations in skeletal perfusion have been linked with changes in bone cell metabolism [5].

Thus, a properly functioning bone vascular system is critical for healthy bone and bone marrow and vascular dysfunction is presumed to contribute to osteopathology.

Dysfunction or dysregulation of the bone vascular network may rest internal to the skeleton (i.e., bone marrow blood vessels) or external (i.e., nutrient arteries and veins that originate outside and penetrate the skeleton).

Thus, the potential influence of bone vascular dysfunction on the development of bone disease is multifaceted and complex.

Previously, the roles of skeletal perfusion [67], spatial redistribution of bone marrow blood vessels [8], bone vascular density [8] and vasomotor responsiveness of the femoral principal nutrient artery (i.e., the primary conduit for blood flow to long bones) [67910] have been considered as contributing factors to altered bone metabolism and mass. What has received little attention, however, has been the role of bone vascular calcification and its potential influence on vascular regulation of skeletal blood flow.

Calcification of blood vessels occurs in several diseases such diabetes, end stage renal disease, atherosclerosis and calciphylaxis [1116] and is present in different sized vessels (e.g., aorta, dermal microvessel, etc.)[17].

Calcification is a complex process and the mechanisms are currently under investigation [17].

During calcification, small crystals of hydroxyapatite deposit in the intima and/or media and often contain pockets of marrow and cartilagenous tissue [1117].

Arteriosclerosis in human bone marrow was first reported in the 1960s and Ramseier suggested that this disease occurs at least a decade earlier in bone marrow in comparison to blood vessels in other organs [18].

In primates fed an atherogenic diet for 20 months, minimal changes occurred in bone arterial morphology of the maxilla and mandible, which presented as fibro-fatty intimal plaques and the occasional replacement of smooth muscle fibers with collagen [18].

These alterations, however, only caused minimal lumen occlusion in the effected bone blood vessels and therefore the declines in blood flow to the maxilla and mandible was attributed to the gross lesions observed in the afferent vasculature (i.e., carotid artery) [18].

Further, some evidence of intraosseous blood vessel calcification presented as heterogeneous staining of the adventitial layer; however, no further physiological or pathological details of the sample were given [19].

The totality of evidence in the literature invited further clarification as to the extent of microvascular calcification in bone.

Examination of bone marrow blood vessels from young and old rats revealed severe pathology that extended beyond calcium deposition, whereby the vessels appeared ossified and bone-like in morphology.

Thus, the purpose of this investigation was to characterize the magnitude of bone marrow blood vessel ossification in relation to patent bone marrow blood vessels and adipocyte volume in the femoral diaphyses of young and old rats.

In addition, this study confirmed the presence of ossified bone marrow blood vessels in human long bones.

DISCUSSION

This study is the first to report ossification of bone marrow blood vessels in young and old rats and in patients with arteriosclerotic vascular disease and peripheral vascular disease with cellulitis.

Bone marrow blood vessel ossification and calcification drastically progressed as a function of age in rats (Figure 2 and Figure 6) and presumably resulted from a transition of vascular cells to an osteogenic phenotype (Figure 4 and Figure 5). Further, the number of patent bone marrow blood vessels declined with age (Figure 7b) and with increased adipocyte volume (Figure 8c).

The pathology presented in this manuscript differs from vascular calcification reported in several disease states [1116]. As observed, bone marrow blood vessels from both rat and human long bones lose a vascular appearance (except for the rod-like structure) and resemble bone, with osteocyte lacunae on the vessel surface (Figures 1b, d and f and Figure 3b and c).

Histological staining revealed that these blood vessels are similar to cortical bone (Figure 5) and are undergoing active bone formation, as evidenced by the presence of osteoid seams (Figure 5E).

To date, however, the cell type responsible for the ossification of bone marrow blood vessels is unknown but may be attributable to adventitial reticular cells, which form a subendothelial layer on the abluminal surface of sinusoidal walls [20].

Adventitial reticular cells (i.e., skeletal stem cells) express alkaline phosphatase and are osteogenic in nature [2122].

The presence of this pathology in both young and old animals suggests that it initiates in youth.

The human femoral diaphyses came from elderly individuals with arteriosclerotic vascular disease and peripheral vascular disease with cellulitis; thus, examination of additional samples varying in age and health status will need to occur.

It seems implausible that ossified vessels maintain patency and the ability to regulate blood flow via vasodilation and/or vasoconstriction.

Since bone vascular density does not always correspond to bone perfusion [23], the loss of vasomotor function in bone resistance arteries and its impact on bone health cannot be overstated.

Declines in vasodilator capacity of the femoral principal nutrient artery were associated with reduced bone mass and vice versa [67924].

Ossification of bone marrow blood vessels presumably results in “microvascular dead space” in regards to loss of vasomotor function as opposed to blood vessel necrosis, since the described pathology is a cellularbased transformation into bone.

Coupled with age-related declines in vasodilator capacity of the nutrient arterial system, the clinical significance of these findings may have therapeutic implications regarding systemic hormonal regulation of bone, delayed fracture healing and the delivery of oxygen, nutrients and pharmaceuticals to bone.

In context of these novel findings, what are the clinical ramifications associated with an enlarging “microvascular dead space” in bone?

Researchers have long recognized the importance of vascular supply for biological activity, including for the skeleton [102526]. Since angiogenesis often, but not always [8], precedes osteogenesis, the circulation of bone is substantively involved in bone cellular regulation and activity [2728].

As hypothetically illustrated in Figure 9, which extends upon theories previously put forth by Colleran et al. (2000) [29], bone marrow blood vessel ossification presumably results in rarefaction and increased capillary distance from bone.

This, in turn, would result in diminished bone blood flow and a centripetal direction to flow. Subsequently, bone marrow ischemia would ensue along with diminished interstitial fluid flow and pressure, and declines in hormonal and factor delivery to bone.

These physiological changes may create hypoxic and acidic conditions and alter osteoblast and osteoclast activity, culminating in reduced bone mass.

Theoretically, the conversion of hematopoietic to fatty marrow may indirectly result from microvascular rarefaction.

Many of the physiological and morphological alterations presented in Figure 9 have been characterized in bone and bone marrow with advanced age.

Thus, it is plausible that these alterations are secondary consequences of blood vessel ossification; consequences that would induce a microenvironment unfavorable for bone accrual and ultimately contribute to declines in bone mass.

The commonality of medullary ischemia in aging long bone has been recognized for several decades [103035].

Bridgeman and Brookes (1996) reported marrow ischemia in femoral diaphyses of aged women and men and a greater reliance upon the periosteal blood supply (i.e., centripetal blood flow) for survival of the diaphyseal cortex [30].

Conversion of diaphyseal flow from centrifugal in youth to centripetal in old age represents an abnormal blood flow pattern [36] and corresponds with declines in bone perfusion reported in animal models and humans [67333739].

Diminished blood flow to bone marrow [673340] and bone [67], reduced vasodilator capacity of bone arteries [67], diminished bone volume [67] and mineral density [40], and replacement of hematopoietic marrow with adipocytes [263340] have been reported in aged rats and humans. Further, the number of bone marrow sinusoids was higher in young healthy individuals vs. individuals >70 years and those with osteopenia [26]. The term sinusoids refer to capillaries in hematopoietic marrow [27]. Thus, the bone vascular system, the volume of hematopoietic marrow and bone mass may be causally related.

The relation between hematopoietic and fatty marrow was not examined in the current investigation; however, higher volumes of marrow adipocytes corresponded with reduced patent bone marrow blood vessel number.

Adventitial reticular cells cover the abluminal surface of marrow sinusoids and conversion of these cells into adipocytes cause sinusoidal collapse, presumably resulting in loss of blood flow [41].

Thus, the agerelated decline in the number of patent bone marrow blood vessels observed in the current study can be explained by increased ossification of bone marrow blood vessels coupled with an augmented volume of marrow adipocytes. Low capillarity is associated with poor bone vitality [2542] and declines in bone vascular density with advanced age have been reported in humans [2631].

Additionally, we demonstrated the importance of the spatial location of bone marrow blood vessels, whereby the smallest vessels (≤ 29 µm in diameter) were spatially closer to sites of new bone formation [8].

This spatial closeness may permit increased nutrient and oxygen exchange between vessels and bone [8] and allow for enhanced delivery of osteoblast and osteoclast precursors to bone remodeling sites [4344].

The closeness and prevalence of capillaries next to cancellous bone remodeling was subsequently confirmed in human bone biopsies [45]. There is continuity among the microvascular beds of the bone marrow, cortex and periosteum [4648] and ossification may disrupt this continuity, creating ischemic and hypoxic areas between bone compartments.

Finally, the vascular supply to bone provides more than just the delivery of oxygen and nutrients. Bone cell modulators (e.g., fibroblast growth factors, colony stimulating factors, endothelin-1, interleukin-1, nitric oxide and prostacyclin) are released by endothelial cells [274950].

Additionally, the vascular endothelium may modulate bone cellular activity through alterations in interstitial fluid flow and pressure [294954]. Nitric oxide and prostacyclin released from endothelial cells in response to shear stress may serve to increase bone formation and diminish bone degradation [5559]. Since the volume and speed of blood delivered to the skeleton is attenuated with advancing age [3336], these reductions may significantly influence the shear forces acting upon bone and endothelial cell membranes, reducing the release of bone regulating factors [29].

In conclusion, this investigation demonstrates, for the first time, ossification of bone marrow blood vessels in both rodent and human long bone.

The creation of “microvascular dead space” would impair the regulation of bone perfusion via vasodilation and/or vasoconstriction or impede the passage of blood. This pathology may arise from a transitioning of vascular cells to an osteogenic phenotype. Ossification of bone marrow blood vessels with advancing age may provide the central link associated with declines in bone perfusion, the centripetal nature of diaphyseal flow, increased bone marrow ischemia, decreased hematopoiesis, augmented bone marrow adiposity and ultimately reduced bone mass (Figure 9). The clinical consequences arising from such pathology may be evident in the difficulties associated with treating bone disease and delayed fracture healing in the elderly.


More information: Rhonda Prisby et al, Discovery of a bone‐like blood particle in the peripheral circulation of humans and rodents, Microcirculation (2019). DOI: 10.1111/micc.12579

Provided by University of Texas at Arlington

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