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Anti-angiogenesis in bone diseases

Anti-angiogenesis in bone diseases

Anti-angiogenesis in bone diseases author publications. Blood— InAnti-angogenesis sunitinib and sorafenib were approved by the FDA for advanced RCC. Article CAS Google Scholar Payne, G. Manara, M. Anti-angiogenesis in bone diseases

Anti-angiogenesis in bone diseases -

Tumor cells and angiogenic endothelial cells use ECM receptors, such as integrin anb3, to bind the surrounding matrix and invade. They also loosen the surrounding matrix by proteolytically degrading the basement membrane using proteinases such as plasminogen activator, matrix metalloproteinase MMP , chymase, or heparanase.

Furthermore, these proteinases regulate angiogenesis by activating or releasing angiogenic stimulators i.

Thus, many investigative antiangiogenesis drugs are targeting angiogenic stimulators, ECM receptors, and ECM proteinases. Under normal physiologic conditions, angiogenesis is well controlled by the local balance between endogenous angiogenesis stimulators and angiogenesis inhibitors, although the regulatory mechanism is still not clear.

Most of the endogenous angiogenic inhibitors can be categorized as matrix derived, such as endostatin, and nonmatrix derived, such as interferons and angiostatin. At least 30 endogenous angiogenesis inhibitors can be detected in blood circulation, indicating that these angiogenesis inhibitors play an important role in maintaining the angiogenic balance under physiologic conditions.

During wound healing, the expression of VEGF, one of the most potent angiogenic stimulators, is significantly upregulated to promote wound healing by restoring blood flow to injured tissues.

As wound healing resolves, the expression of VEGF is downregulated and most angiogenic capillaries regress, resulting in a residual normal vascularity.

Deficient production of angiogenic stimulators turns off the angiogenesis switch and leads to insufficient angiogenesis. Inordinate production of angiogenic stimulators turns on the angiogenesis switch and drives excessive angiogenesis.

Both insufficient and excessive angiogenesis contribute to the pathogenesis of many major diseases. Under pathologic conditions, insufficient angiogenesis occurs in coronary artery disease, stroke, and chronic wounds.

Excessive angiogenesis occurs mostly when diseased cells, such as inflammatory and tumor cells, produce abnormal amounts of angiogenic stimulators, overwhelming the effects of endogenous angiogenesis inhibitors, thus turning on the angiogenesis switch.

Most important, during cancer development the human body loses control over the balance between angiogenesis stimulators and inhibitors, which leads to excessive angiogenesis that feeds the tumor growth and facilitates tumor metastasis.

Also of clinical interest, colorectal and breast cancer patients specifically showed increased concentrations in VEGF-A and MMP-9 plasma levels due to malignancy. These levels are reduced after the tumor is removed, which significantly decreases the extent of angiogeneses.

Excessive angiogenesis is seen in diseases such as solid tumor cancers, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and psoriasis, as well as other diseases.

In these conditions, new blood vessels feed diseased tissues and destroy normal tissues. In the case of cancer, tumor cells produce and secrete excessive amounts of many potent angiogenic stimulators, such as VEGF, placental growth factor PlGF , stromal-cell—derived factor 1, and angiopoietin These angiogenic stimulators will activate the complicated multistep angiogenesis process surrounding the tumor microenvironment.

New evidence indicates that these angiogenic factors also stimulate the mobilization of cells at distant sites, including bone marrow, into circulation to promote vascularization. Angiogenesis is a tightly regulated multistep process. Many enzymes, growth factors, ECM proteins, ECM receptors, and their signal transduction pathways involved in the regulation of angiogenesis can be potential targets for angiogenesis therapy.

Drugs based on blocking monoclonal antibodies and chemical inhibitors are being developed to counter the effect of angiogenesis growth factors. Other positive regulators are angiopoietin-1, angiotropin, angiogenin, epidermal growth factor EGF , granulocyte colony-stimulating factor, interleukin IL -1, IL-6, IL-8, and platelet-derived growth factor PDGF.

Since VEGF plays an essential role in stimulating tumor angiogenesis, blocking VEGF-mediated signaling pathways has been one of the major strategies for antiangiogenesis therapy.

Currently, there are six members in the VEGF family i. These VEGF proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases known as VEGF receptor VEGFR -1, -2, and Monoclonal antibodies against VEGF or VEGFR and small molecule inhibitors of VEGFR tyrosine kinase and its downstream signal transduction pathway are some of the major antiangiogenesis therapeutic agents.

The first successful treatment of an angiogenesis-dependent disease occurred in , when the drug interferon alfa-2a was used to suppress angiogenesis by inhibiting VEGF and bFGF production, which led to regression of abnormal blood vessels growing in the lungs of a boy with pulmonary hemangiomatosis.

In February , bevacizumab Avastin , a humanized blocking monoclonal antibody for VEGF, was approved to treat metastatic colorectal cancer in combination with 5-FU. Since then, bevacizumab in combination with standard chemotherapy agents has been found efficacious in clinical trials of non—small cell lung cancer NSCLC , renal cell carcinoma RCC , glioblastoma, ovarian cancer, and breast cancer.

More recently, aflibercept VEGF Trap in combination with standard chemotherapy regimens is undergoing phase II and phase III clinical trials in the treatment of advanced solid tumors in five different cancers: colorectal cancer, NSCLC, prostate cancer, pancreatic cancer, and gastric cancer.

Aflibercept is a fused protein comprised of segments of the extracellular domains of human VEGFR-1 and VEGFR-2, and constant region Fc of human immunoglobulin G IgG.

Aflibercept inhibits angiogenesis by functioning as a soluble decoy receptor to trap VEGFs. In addition to the ligand blocking agents, antiangiogenesis drugs are also being developed to block the signal transduction pathway for angiogenesis stimulators.

Several small molecular-weight receptor tyrosine kinase RTK inhibitors such as sunitinib Sutent and sorafenib Nexavar , have been developed to target the signal transduction pathway of angiogenic stimulators, such as VEGF, EGF, and PDGF.

In , both sunitinib and sorafenib were approved by the FDA for advanced RCC. In October , the FDA granted approval to pazopanib Votrient for the treatment of patients with advanced RCC. A variety of other small-molecule RTK inhibitors targeting the VEGF and EGF receptors signal transduction pathway have been approved by the FDA for the treatment of solid tumor cancers, including gefitinib Iressa and erlotinib Tarceva.

Some clinical studies indicate that nilotinib is active in GIST resistant to both imatinib and sunitinib. Other small-molecule agents under clinical investigation include motes-anib, vatalanib, and vandetanib. The discovery of downstream signal-transduction pathways for RTK has also led to the development of many newly targeted agents.

As one of the key protein kinases controlling signal transduction from various growth factors and upstream proteins to the level of mRNA translation and ribosome biogenesis , mammalian target of rapamycin mTOR plays a critical role in regulating cell cycle progression, cellular proliferation and growth, and angiogenesis.

Temsirolimus is recommended as first-line treatment for patients with poor-prognosis metastatic RCC. In , the FDA approved everolimus Afinitor, also known as RAD as the second drug in the class of mTOR inhibitors for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib.

Interestingly, research on some of the previously approved chemotherapeutic agents, such as doxorubicin and cisplatin, demonstrates that they inhibit VEGF production. Thalidomide inhibits angiogenesis mediated by VEGF and bFGF, and studies have shown that thalidomide in combination with dexamethasone has increased the survival of multiple myeloma patients.

In addition to the chemotherapeutic and endogenous angiogenesis inhibitors, natural sources with antiangiogenic properties include tree bark, fungi, shark muscle and cartilage, sea coral, green tea, and herbs such as licorice, ginseng, cumin, and garlic.

In total, more than angiogenesis inhibitors have been discovered to date. Although they may not necessarily directly kill tumor cells, angiogenesis inhibitors significantly enhance the efficacy of standard chemotherapy and radiation therapy by inhibiting tumor growth and tumor metastasis.

Therefore, this type of therapy may need to be administered over a long period of time. Since antiangiogenesis therapy is a targeted therapy aimed specifically at the angiogenic stimulators and the angiogenic microvascular endothelial cells, antiangiogenesis therapy usually produces only mild side effects and is less toxic to most healthy cells.

But as angiogenesis is important in wound healing and reproduction, long-term treatment with antiangiogenic agents could cause problems with bleeding, blood clotting, heart function, the immune system, and the reproductive system, with some side effects still unknown.

Since the time when Dr. Folkman pioneered the concept of antiangiogenesis therapy for cancer treatment four decades ago, angiogenesis research has gained tremendous interest in both academic research institutions and the pharmaceutical industry.

Although hundreds of antiangiogenesis therapeutic agents are under investigation, the FDA currently has approved only 14 anticancer drugs with recognized antiangiogenic properties.

Based on therapeutic targets, these agents can be grouped into four major categories: monoclonal antibody therapies, small-molecule RTK inhibitors, mTOR inhibitors, and unknown mechanisms.

Monoclonal Antibodies: These agents work by binding biologically active forms of angiogenic stimulators or their receptors and inhibiting endothelial cell proliferation and angiogenesis. Adverse effects of monoclonal antibody therapy are usually fairly mild.

Side effects can include fever, chills, weakness, headache, nausea, vomiting, diarrhea, low blood pressure, and rashes TABLE 1. Small-Molecule RTK Inhibitors: This is currently the largest class of drugs that block angiogenesis. These agents have the advantages of hitting multiple targets, oral administration, and potential for lower cost.

Lack of target specificity leads to unexpected toxicity but also promising efficacy. Hypertension, hemorrhage, and cavitation are common toxicities among this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with RTK inhibitors.

A major adverse effect with the EGF RTK inhibitors is an acnelike rash TABLE 2. mTOR Inhibitors: These agents represent a third, smaller category of antiangiogenic therapies with two FDA-approved agents, temsirolimus Torisel and everolimus Afinitor. Other common adverse events for temsirolimus and everolimus include fatigue, stomatitis, diarrhea, hypophosphatemia, low red blood cells and platelets, and peripheral edema.

These adverse events are commonly reversible upon treatment discontinuation. Less common symptoms are renal insufficiency, interstitial pneumonitis, and low white blood cells TABLE 3. Unknown Mechanisms: Bortezomib Velcade and thalidomide Thalomid may indirectly inhibit angiogenesis through mechanisms that are not completely understood TABLE 4.

Antiangiogenesis therapy represents one of the most significant advances in clinical oncology. It has sparked tremendous interest in angiogenesis research in both academic research institutions and the pharmaceutical industry for the past two decades.

The FDA has approved 14 anticancer drugs with recognized antiangiogenic properties. More research is needed to fully understand the biological mechanisms of tumor angiogenesis to optimize this new cancer treatment strategy.

Next-generation medications are in development to increase the target specificity and to investigate possible treatments across the spectrum of solid tumors. Although the majority of the currently approved antiangiogenesis drugs only offer a modest survival benefit in a limited patient population, they have paved the way for the development of an optimized antiangiogenesis strategy and improved cancer treatments.

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Angiogenesis: a target for cancer therapy. Curr Pharm Des. Fidler IJ, Lee ME. Neoplastic angiogenesis—not all blood vessels are created equal. N Engl J Med. Ma JX, Zhang SX, Wang JJ. Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications.

Curr Diabetes Rev. Zaman K, Driscoll R, Hahn D, et al. Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs.

conservative therapy. Int J Cancer. During acute inflammation, IFN-α promotes activation and proliferation of BM ECs is mediated by increased VEGF production by hematopoietic cells such as HSCs Prendergast et al. In line with increased angiogenic VEGF levels, enhanced number of sinusoids and luminary are found in the inflamed BM.

Inflammation also increases hypoxic regions in long bones, which may contribute to enhanced bone angiogenesis Vandoorne et al. Furthermore, the BM endothelium shows high vascular permeability and leakiness during inflammation, caused by the opening of tight junctions in order to promote trans -endothelial migration of immune cells Prendergast et al.

Inflammation-driven niche alterations show many similarities to changes in the aged BM niche. Elevated levels of proinflammatory cytokines have been associated with aging of the BM microenvironment and age-related myeloid malignancies.

Both inflammation and aging induce a myeloid differentiation bias and impair HSC self-renewal capacity Kovtonyuk et al. Serum levels of proinflammatory cytokines such as IL-1, IL-6, and TNF-α are upregulated in the aged population, and this upregulation may underlie the high myelopoiesis and adipogenesis that occurs in aged BM Hasegawa et al.

Myeloid cells and adipocytes represent significant sources of proinflammatory cytokines, suggesting a positive feedback loop between aging and inflammation.

During aging, increased levels of pro-inflammatory cytokines create a chronic proinflammatory state that further enhances myeloid skewing of HSCs Ergen et al. In addition, adipogenic differentiation of perivascular MSCs may also promote myelopoiesis and cytokine production that is observed during aging Kovtonyuk et al.

To uncover the contributions of vascular and perivascular cells during age-associated inflammation, the inflammaging process needs further investigation. Alterations in vascularization in connective tissues including bone have been described in a number of arthropathies; neoangiogenesis has been proposed as a pathological process in some.

Here, rheumatoid arthritis RA as an exemplar of chronic inflammatory arthritis and osteoarthritis as the commonest degenerative joint disorder are given. Rheumatoid arthritis is the most common form of chronic inflammatory arthritis and results in joint inflammation, articular bone loss and increased cardiovascular morbidity and mortality Totoson et al.

RA is characterized by increased articular angiogenesis and synovial inflammation that damages affected joints Walsh et al. Proinflammatory cytokines from inflamed joints activate ECs by inducing endothelial expression of VCAM1, intracellular adhesion molecule 1 ICAM1 , E-selectin and other adhesion molecules Klimiuk et al.

Cell adhesion molecules facilitate leukocyte and fibroblast invasion into the joint and shift ECs into a proinflammatory state Klimiuk et al. Endothelial activation and systemic inflammation trigger endothelial dysfunction, which is characterized by impaired vasodilation.

Endothelial dysfunction crucially contributes to the development of accelerated atherogenesis and cardiovascular mortality in RA Ulker et al. Impaired vasodilation increases the blood flow and pressure that is transmitted into microvessels, thereby damaging vascular beds Totoson et al.

Multiple studies have identified a decreased bioavailability of vasoactive nitric oxide NO underlying impaired vasodilation in RA Wilcox et al. During the early stage of RA, this is compensated by increased NO synthase activity that is lost with persistence of inflammation and the onset of endothelial dysfunction Totoson et al.

Transcriptomic analysis of human synovial fibroblasts has identified a distinct subpopulation characterized by the expression of Podoplanin, THY1, and Cadherin Mizoguchi et al.

This fibroblast subpopulation is significantly upregulated in RA patients, localizing and expanding near the blood vessels and secreting proinflammatory cytokines Mizoguchi et al.

Upregulation of NOTCH3 and Notch target genes via blood vessels is found in active RA Wei et al. Deletion of Notch3 or blocking of NOTCH3 signaling blocks fibroblast expansion, alleviates inflammation and prevents damage of inflamed joints, indicating a critical role for Notch3 signaling in regulating synovial fibroblast differentiation, expansion and disease activity Wei et al.

Levels of neoangiogenesis in RA appear to be closely linked to levels of synovial inflammation and to pain experienced, making it a viable therapeutic target in this disease Paleolog, ; Fransès et al. Proinflammatory cytokines also modulate osteoclastogenesis and impair osteoblastic bone repair, facilitating articular bone loss in RA if inflammation is not controlled pharmacologically Karmakar et al.

At a local level this can lead to bone erosion, loss and deformity, and systemically to osteopenia and osteoporosis. Controlling inflammation by inhibiting TNF-α significantly improves flow-mediated vasodilation and disease activity and may reduce cardiovascular morbidity Jacobsson et al.

Osteoarthritis OA is a chronic joint disease and considered the most common form of arthritis Ashford and Williard, ; Vincent and Watt, ; Hunter and Bierma-Zeinstra, OA is characterized by articular cartilage loss and new bone formation osteophytosis associated with sclerosis of underlying bone.

BM abnormalities are seen including BM edema BME , abnormal osteogenesis and a reported increase in subchondral angiogenesis Felson et al. Some believe that these subchondral bone changes contribute to the progressive degeneration of cartilage, although this is not well understood Dyke et al.

Disruption of subchondral blood flow impairs diffusion of nutrients to the articular cartilage, resulting in the death of osteocytes and joint damage Zhen et al. OA has also been associated with increased cardiovascular comorbidity and mortality Turkiewicz et al.

One study of patients with knee OA revealed an association between OA radiological severity and increased arterial stiffness Tootsi et al. Obesity is known to increase the incidence and progression of OA King et al. Multiple studies demonstrate increased adipokines including serum leptin levels associated with the disease de Boer et al.

Leptin has been shown to upregulate proteolytic enzymes such as MMP-1 and MMP-3 in articular cartilage and correlates with their levels in the synovial fluid of OA patients, suggesting a potential for an enhanced catabolic effect on OA cartilage Koskinen et al.

Inflammatory cytokines such as TNF-α, IL-6, IL, and IFN-γ have been reported to be upregulated in the synovial fluid, the articular cartilage and synovium of OA patients Zhou et al. Inflammatory signaling in connective tissues which can be driven by such inflammatory cytokines as well as by mechanical stress to tissues is associated with protease expression such as aggrecanases and metalloproteinases MMPs and chemokines, driving cartilage degeneration Findlay and Kuliwaba, Increased activation of TGF-β1 in murine and human OA effectively recruits MSCs and type H vessels, causing OA-characteristic abnormal bone formation and augmented subchondral angiogenesis Zhen et al.

Osteoblast-specific overexpression of TGF-β1 induces murine OA Blaney Davidson et al. Increased subchondral angiogenesis may contribute to OA progression Hamilton et al.

Type H vessels can drive OA progression by releasing proteases such as MMP-2, MMP-9, and MMP, which promote the resorption of cartilage matrix and its degeneration Romeo et al.

Articular chondrocytes in vitro stimulate excessive subchondral type H vessel formation by mechanistic target of rapamycin complex 1 mTORC1 -mediated VEGFA production Lu et al. Reciprocally, vascular-derived nutrients promote chondrocyte and mTORC1 activation and VEGF production, further enhancing subchondral angiogenesis Lu et al.

Inhibition of mTORC1 is able to reduce this pathological angiogenesis, thereby delaying disease progression Lu et al. During later stages of OA, articular cartilage, synovium and subchondral bone show increased levels of VEGF Hamilton et al. Synovial VEGF levels have also been found to correlate with disease severity and pain in patients with knee OA, potentially implicating VEGF as a biomarker for OA pathogenesis Gaballah et al.

Sensory nerves grow along new blood vessels in osteoarthritic joints, eventually reaching non-calcified articular cartilage, osteophytes and menisci, and may be a source of pain from all of these structures.

Angiogenesis could therefore be a source of pain in OA Mapp and Walsh, Inflamed synovium has upregulated levels of the neurotrophin nerve growth factor NGF Aloe et al. NGF signals by way of binding its two receptors TrkA and p NGF signaling is known to be increased in the context of inflammation, for example in RA Skaper, In OA, NGF stimulates sensory nerve growth into vascular channels of articular cartilage and subchondral bone, contributing to arthritic pain Suri et al.

Neutralizing NGF with monoclonal antibodies in both murine and human OA leads to reduction in joint pain Lane et al. Substantial expression of NGF receptors TrkA and p75 is found in rat bone Nencini et al.

NGF injection into rat bone rapidly activates nociceptors and produces an acute behavioral pain response, implicating NGF in inflammatory bone pain Nencini et al. NGF also functions as an angiogenic factor. ECs express TrkA and p75 and administration of NGF induces capillary sprouting and increased neuronal VEGF expression in newborn rats Calzà et al.

VEGF activates these same pathways, perhaps suggesting a joint role for NGF and VEGF in the regulation of angiogenesis Nico et al. Osteoporosis is a metabolic bone disease that results in progressive bone loss and fragility Cooper et al. It is characterized by the imbalance of osteoblast-mediated bone formation and osteoclast-mediated bone resorption with resultant reduction in bone mass, disrupted microarchitectural integrity and increased risk of fracture Sözen et al.

Postmenopausal women have an increased susceptibility to osteoporosis, in part due to the fall in estrogen levels at the time of menopause that leads to a higher rate of bone resorption than formation Ji and Yu, Aging in both men and women is also associated with increased risk of osteoporosis.

Multiple studies have shown a reduction in bone vasculature and bone-forming cells in mouse models of osteoporosis Weinstein et al. Specifically, age-related loss of type H endothelium appears to play an important role in the pathogenesis of osteoporosis Ding et al. Significant reduction of type H vessels is observed in ovariectomized female mice, a commonly used experimental model of postmenopausal osteoporosis Wang et al.

Likewise, the decline of human type H endothelium is observed in women after menopause Zhu et al. A reduction of type H vessels, mature osteoblasts and osteocytes is also observed in a mouse model of glucocorticoid-induced osteoporosis GIO Yang et al.

Glucocorticoids decrease blood flow and inhibit angiogenesis by reducing VEGF levels Wang et al. Pre-osteoclast PDGF-B secretion induces type H vessel growth and angiogenesis and osteogenesis Dou et al.

The osteoclast-derived cathepsin K decreases pre-osteoclast secretion of PDGF-B; this impairs the recruitment of mesenchymal and endothelial progenitors to bone remodeling sites and reduces bone and blood vessel formation Yang et al.

Interestingly, knockout of cathepsin K in GIO mice prevents PDGF-B reduction and loss of osteoblasts, osteoclasts, and type H ECs. In line with these findings, inhibition of cathepsin K via administration of an inhibitor L prevents osteoporosis and maintains osteoblasts and bone volume Yang et al.

Moreover, cathepsin K inhibition increases PDGF-B and preserves type H vessel by enhancement of endothelial VEGF production Yang et al. Another study implicated a role for another osteoblast-derived proangiogenic factor slit homolog 3 protein SLIT3 in osteoporosis-associated loss of bone mass and vasculature Figure 3 and Table 1.

Intravenous SLIT3 injection in ovariectomized mice reverses bone loss and augments type H ECs Xu R. Bone fracture disrupts the typical bone architecture, vasculature, and surrounding tissue.

Fractures are often accompanied by blood vessel damage, thereby causing hemorrhage, local hypoxia and susceptibility to infection Marenzana and Arnett, ; Baker et al.

The initial proinflammatory state stimulates cell proliferation and differentiation via expression of IL-1 Lange et al.

A soft callus is formed soon after fracture which stabilizes the site of injury Baker et al. Local hypoxia and high lactate levels after fracture upregulate the expression of HIF1-α and its downstream target VEGF that stimulate angiogenesis and osteogenesis and replace soft callus by vascularized hard callus Wang et al.

Disruption of osteoblast-derived HIF1-α delays callus formation and impairs fracture healing Wang et al. Angiogenesis is considered to be essential in fracture repair Hausman et al. During the repair phase, VEGF stimulates the regrowth of blood vessels into the site of injury to restore normal oxygen and nutrient supply and activate osteoblast function Marenzana and Arnett, ; Figure 1.

While inhibition of VEGFR1 and VEGFR2 impairs osteogenesis and chondrogenesis and reduces callus formation Jacobsen et al. TNF-α administration has also been shown to promote fracture repair by recruiting muscle-derived stromal cells and promoting osteogenic differentiation Glass et al.

Regrowth of sensory nerve fibers is stimulated by NGF, creating pain sensation. NGF also stimulates VEGFA-mediated revascularization and promotes ossification via TrkA-mediated communication between sensory nerves and osteoblasts Tomlinson et al.

Inhibition of TrkA signaling reduces nerve regrowth and revascularization, delaying ossification of fracture calluses Li et al. With revascularization of the injury site, new bone tissue is formed directly via progenitor differentiation into osteoblasts intramembranous ossification and indirectly via cartilage intermediate endochondral ossification Hu et al.

During endochondral ossification, VEGF binds to the cartilage matrix until its release by MMPs. MMPs degrade and remodel the extracellular matrix ECM and are highly expressed during fracture repair Bahney et al. Knockout of MMP-2 delays bone remodeling, while MMP-9 and MMP knockouts impair cartilage remodeling, vascularization and bone formation Colnot et al.

Interestingly, administration of recombinant VEGF rescues these phenotypes, emphasizing the importance for MMP mediated fracture revascularization of VEGF availability Colnot et al. ECM proteins such as thrombospondin and osteopontin also modulate fracture vascularization.

Thrombospondin has an antiangiogenic function Bahney et al. Accordingly, thrombospondin knockout mice exhibit enhanced angiogenesis and bone regeneration Taylor et al. In contrast, osteopontin is a proangiogenic factor, and delays fracture neovascularization when deficient Duvall et al.

During the remodeling phase, callus and vessels are reduced toward pre-injury levels, and the cortical and medullary structure is restored Baker et al.

The remodeling process consists of a complex interplay between osteoclasts, osteoblasts and vasculature and is driven by high levels of proinflammatory cytokines such as IL-1 and TNF-α Mountziaris and Mikos, ; Baker et al.

Blockade of angiogenesis during this phase significantly increases callus formation and inhibits callus remodeling Holstein et al.

During the remodeling phase, BM stem cells BMSCs form a source of osteoclasts, while a subset of periosteal stem cells differentiates into chondrocytes and osteoblasts Colnot, ; Baker et al.

Multiple studies have indicated an MSC-function for pericytes, enabling them to differentiate into osteoblast and chondrocyte progenitors Diaz-Flores et al.

Comorbidities such as aging significantly delay fracture repair, presumably due to underlying vascular dysfunction Bahney et al. Blood vessel density was significantly decreased in fractures of aged and middle-aged mice compared to young mice, coupled with reduced cartilage volume Lu et al.

Moreover, expression levels of VEGF, HIF-1α, MMP-9, and MMP were significantly reduced in early fracture calluses of aged mice, likely underlying the observed delay of angiogenesis Lu et al.

The BM provides a unique microenvironment not only for HSCs but also for tumor cells. Similar to HSCs, cancer stem cell CSC activity relies on signals from the BM microenvironment Plaks et al.

Primary tumor cells and host cells secrete various factors that support CSC survival and dissemination, creating a pre-metastatic microenvironment Kaplan et al. Further, CSCs can modulate angiogenesis by producing proangiogenic factors such as VEGFA Chand et al.

Here, malignant alterations of the BM niche in hematologic tumors, primary bone tumors and bone metastasis are highlighted. Acute myeloid leukemia AML is the most common type of leukemia. AML patients show upregulated VEGF levels and BM hypervascularity, associated with poor prognosis Bosse et al.

Besides inducing tumor angiogenesis, VEGFA also facilitates chemotactic cell migration and increases vascular permeability Nagy et al. Studies using intravital two-photon microscopy have demonstrated various structural and functional maladaptations of bone vasculature in AML.

Vasculature of mice with AML show disorganized vasculature, reduced vessel diameter and increased microvascular density within the BM and reduced vessel density in the endosteal region Passaro et al.

Also, AML mice exhibit functional vascular abnormalities; perfusion is impaired, while angiogenic VEGFA levels, hypoxia and vascular leakiness are increased Passaro et al. These findings are supported by the transcriptomic analysis of ECs after human AML engraftment, revealing reduced endothelial expression of tight junction components that are required for vessel integrity Passaro et al.

Xenografts of AML patients show an increase in perivascular hypoxia that increases endothelial ROS and NO levels, impairs HSC function and promotes cell death and HSC egress from the BM Passaro et al. Inhibition of endothelial remodeling in AML rescues HSC loss and increases chemotherapeutic efficiency and survival Duarte et al.

Osteosarcoma is the most common primary bone tumor Broadhead et al. It is considered highly vascularized and is characterized by early metastatic dissemination through intratumoral vessels. The lungs and bone represent the most common sites of metastasis Broadhead et al.

Microvascular density analysis of osteosarcoma patient biopsies revealed increased survival rates and responsiveness to chemotherapy in patients with low osteosarcoma vascularization Kunz et al.

Similar to other blood and bone cancers, osteosarcoma cells have a strong angiogenesis-inducing function that increases with intratumoral vessel size and length Uehara et al. Tumor angiogenesis is facilitated by a hypoxic and acidic microenvironment around proliferating osteosarcoma cells, which stimulates HIF-1α and subsequent VEGF upregulation Broadhead et al.

Antiangiogenic factors and proteins, including thrombospondin-1, TGF-β Ren et al. PEDF has shown promising results as an anti-tumor agent Table 1. Multiple studies have demonstrated suppression of tumor growth, angiogenesis and metastasis upon overexpression Ek et al.

Upregulation of the proangiogenic protein CYR61 in osteosarcoma, crucially contributes to primary tumor vascularization Habel et al.

Silencing CYR61 decelerates tumor growth and reduces tumor vasculature and the expression of proangiogenic factors, including VEGF, PECAM and angiopoietins.

Simultaneously, silencing of CYR61 upregulates thrombospondin-1 and other antiangiogenic factors Habel et al. Interestingly, CYR61 downregulation is associated with decreased MMP2 expression, an essential regulator of metastatic osteosarcoma capacity Habel et al.

MMPs play an important role in degrading the ECM to enable tumor invasion into the surrounding tissue Oh et al. Membrane-type 1 matrix metalloproteinase MT1-MMP is crucial for cell migration and has been shown to promote tumor cell migration and invasion Itoh et al.

They also remodel the vascular network and decrease vessel wall integrity to allow tumor cell passage into the bloodstream Oh et al.

Tumor cells further express NGF, which has similar angiogenic effects as VEGFA Nico et al. NGF induces tumor angiogenesis by enhancing endothelial growth, migration and permeability Romon et al.

Inhibition of NGF with siRNA significantly reduces tumor progression and angiogenesis in breast cancer Adriaenssens et al. Both VEGFA and NGF promote MMP production Pufe et al.

Trans -differentiation of CSCs into pericytes is reported to occur via endothelial production of CXCL12 and TGF-β Cheng et al. The acidic tumor microenvironment increases CXCL12 production Nakanishi et al. Vascular mimicry has been described in numerous types of solid tumors, including osteosarcoma and Ewing sarcoma and is involved in cancer progression, dissemination and metastasis Ge and Luo, The BM vascular niche acts as a protective and supportive site for cancer cells Ninomiya et al.

BM hematopoietic cells express VEGFR1, thereby forming a pre-metastatic niche that attracts cancer cells Kaplan et al. Due to its intrinsically high vascular density, the BM enables increased crosstalk between cancer cells and ECs, supporting tumor cell proliferation Virk and Lieberman, Endothelial thrombospondin-1 production creates a stable BM vascular niche for disseminated tumor cells DTCs.

Integrated into this niche, DTCs remain in a dormant state over a long period Ghajar et al. The large vessel diameter and low sinusoidal blood flow of the BM vasculature facilitate DTC dormancy and therapy resistance Kopp et al.

Co-culture of AML cells with BM ECs increases the proportions of quiescent AML cells Cogle et al. Integrin-mediated interaction between DTCs and endothelial-derived von Willebrand factor and VCAM1 is a crucial factor in DTC chemoresistance Carlson et al.

Inhibiting these interactions via integrin-blocking antibodies sensitizes DTCs to chemotherapy and prevented bone metastasis Carlson et al.

Endothelial PDGF-B signaling is another key regulator of tumor cell dormancy and therapy resistance Singh et al. Radiation and chemotherapy induces a bone-specific expansion of pericytes via endothelial PDGF-B signaling.

Expanding pericytes further support therapy resistance of quiescent DTCs in the BM by secreting quiescence-inducing factors such as CXCL12 Singh et al.

DTC dormancy is guided by microenvironmental cues similar to those involved in adult stem cell dormancy Risson et al. For instance, MSC-specific deletion of CXCL12 promotes LSC division and expansion while reducing normal HSC numbers Agarwal et al.

Remodeling of the tumor BM microenvironment such as the age-related loss of perivascular PDGF-B signaling reactivates dormant DTCs and induces their proliferation Ghajar et al. Therefore, bone is one of the most common sites of metastasis even after decades of latency Kusumbe, ; Singh et al.

Quiescent DTCs retain transcriptional plasticity that enables them to reactivate different regulatory programs, allowing reversible growth arrest and survival Risson et al.

Induction of cell cycle expression in AML cells renders them susceptible to therapy, leading to tumor regression Bosse et al. Moreover, inhibiting VEGFA signaling improves chemotherapy efficiency Poulos et al. Furthermore, bone metastasis is the most common cause of pain in cancer Mercadante, NGF plays an important role in modulating bone cancer pain and is expressed by tumor, immune and inflammatory cells Dollé et al.

Treatment with an anti-NGF antibody significantly reduces bone cancer pain behaviors in a mouse model of femoral osteosarcoma Sevcik et al. The NGF monoclonal antibody tanezumab has also shown promising results in the treatment of chronic pain in patients with metastatic bone cancer Sopata et al.

Radiation is a commonly used therapy for hematological malignancies, that causes tissue damage, reduces hematopoietic populations and promotes HSC mutations.

Despite its common prescription, the effects of radiation therapy on the BM microenvironment remain poorly understood. Microcomputed tomography and immunohistological studies of irradiated murine bone show a severe decline of bone volume with an increase in number and activity of bone-resorbing osteoclasts Willey et al.

Radiation also damages the BM vasculature, particularly depleting sinusoidal ECs and increasing vascular dilation and permeability. Transcriptomic analysis revealed substantial changes in EC transcriptomes in response to radiation, including genes associated with vascular niche function Chen et al.

Furthermore, expansion of Apln-expressing ECs occurs upon radiation treatment. This subpopulation of bone ECs has the ability to generate arterial ECs and contribute to BM vascular regeneration after irradiation Chen et al.

Moreover, radiation significantly enhances the BM adipocyte compartment Hooper et al. Regeneration of sinusoidal ECs post-irradiation is partially mediated by VEGFR2 signaling and is essential for the restoration of normal hematopoiesis Hooper et al. Another commonly used therapy for hematological malignancies is chemotherapy.

Most chemotherapies have similar effects on the BM microenvironment as radiation, depleting osteoblasts, increasing adipocyte numbers and damaging BM endothelium Zhou et al. Tracking gene expression profiles of BM cells after 5-FU treatment revealed an upregulation of adipogenesis-associated genes accompanied by a downregulation of osteolineage-associated genes.

Chemotherapy is further associated with a general loss of vascular and perivascular cells in the BM Tikhonova et al. Myeloablation via radiation or chemotherapy increases expression of inflammatory cytokines such as IL-6, G-CSF, and GM-CSF that promote HSC differentiation and lineage commitment Rafii et al.

In contrast, myeloablation downregulates vascular Notch delta ligands, Dll1 and Dll4. Dll4 is a regulator of hematopoietic differentiation, causing transcriptional reprogramming and myeloid priming of HSCs in its absence Tikhonova et al.

After myeloablation, ECs upregulate their production of VEGFA, FGF-2, and other angiogenic factors to facilitate HSC regeneration.

These angiocrine factors activate Akt and upregulate the Notch ligand Jagged-1 Kobayashi et al. Transplantation of Akt-activated BM ECs enhances hematopoietic recovery after myeloablation Poulos et al.

Further, co-activation of endothelial Akt with MAPK induces HSC differentiation and expands the hematopoietic progenitor pool, demonstrating a key role of Akt in hematopoietic regeneration Kobayashi et al. Collectively, these findings demonstrate significant BM vascular niche remodeling during hematological malignancies, myeloablation and hematopoietic recovery.

Bone marrow ECs and perivascular cells form a heterogeneous and nurturing microenvironment for stem and progenitor cells of various lineages and produce various factors to support hematopoiesis and osteogenesis. Aging, inflammation and other stress factors can alter vascular morphology and function and disrupt angiocrine crosstalk in vascular niches.

Pathological processes including arthritis, osteoporosis, bone pain and cancer are associated with bone angiogenesis. Vascular niche remodeling in response to stress can severely affect HSCs, hematopoiesis and bone lineage cells and may contribute to metastatic relapse and chemoresistance.

Detailed knowledge of the BM microenvironment could provide new insights into pathological processes in the skeletal system and holds the potential to provide strategies for the clinical management of hematological disorders and bone diseases.

Thus, future research should further unravel the impact of stress on the BM vascular niche to improve our understanding of vascular niche function and interactions. SS wrote the original draft. SS and JC prepared the figures. AK, JC, and FW reviewed and edited the manuscript.

AK designed the review structure and figures. All authors contributed to the article and approved the submitted version. FW is a UKRI Future Leaders Fellow S and a member of the Centre for Osteoarthritis Pathogenesis Versus Arthritis grants and She was supported by the NIHR Oxford Biomedical Research Centre.

The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Thank you for visiting Anti-angiogenesi. You are Herbal vitality pills a browser version with limited support Meal ideas for performance CSS. Ciseases obtain Anti-angiotenesis best experience, we recommend you Herbal vitality pills a more up to date kn or bonr off compatibility mode in Internet Anti-angiogenesis in bone diseases. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Different tissues have different endothelial features, however, the implications of this heterogeneity in pathological responses are not clear yet. To highlight a possible contribution of organ-specific endothelial cells ECswe compare ECs derived from bone and skeletal muscle of the same OA patients. OA bone ECs show a pro-inflammatory signature and higher angiogenic sprouting as compared to muscle ECs, in control conditions and stimulated with TNFα. The bone marrow Anti-angiogenesis in bone diseases idseases niche microenvironments harbor stem and progenitor iin of gone lineages. Bone angiogenesis is Anti-angiogenesls and involves tissue-specific signals. The nurturing Energy drinks for endurance niches in the BM are complex Anti-angiogenesis in bone diseases heterogenous bome Anti-angiogenesis in bone diseases distinct vascular diseaxes perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease.

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