Biology subjects

McNamara, L. M.

Publications and source records attributed to McNamara, L. M..

4 recordsLinked to original sources

bioRxiv2025

Osteoblasts Exert a Pro-Tumorigenic Effect on Breast Cancer Spheroids Through CXCL5/CXCR2 Signaling In 2D And 3D Bone Mimetic Cultures

Bone provides a favorable niche for breast cancer colonization and metastatic progression. Breast cancer cells are attracted to the bone microenvironment where they induce bone cells to resorb bone, which enhances tumor cell proliferation in a positive feedback loop often referred to as the vicious cycle. While this phenomenon is established, the molecular interactions between cancer cells and bone cells are not well defined. CXCL5/CXCR2 signaling has recently been shown to promote breast cancer colonization to the bone. Here, we investigate the effects of osteoblasts and osteocytes on breast cancer cell proliferation in engineered two- and three-dimensional models. We observed that osteoblasts and osteocytes induce proliferative effects on cancer cells. Specifically, bone cells increase cancer proliferation in 2D culture and osteoblasts increase cancer growth more than osteocytes in 3D models. Moreover, osteocyte interaction with cancer cells in 3D models are stiffness dependent. We show that these effects depend on the CXCL5/CXCR2 signaling axis. Taken together, we demonstrate that osteoblasts drive cancer growth in a bone metastatic niche and that this effect can be rescued with CXCL5/CXCR2 inhibition.

bioengineering↗

bioRxiv2024

Mechanobiological cues to bone cells during early metastasis drive later osteolysis: a computational mechanoregulation framework prediction

Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.

cancer biology↗

bioRxiv2024

Early Intervention with Low-Dose Sclerostin Antibody Therapy can Reduce Osteocyte-mediated Secondary Mineralization after initial bone loss in Ovariectomised Rats

Neutralizing sclerostin antibodies (Scl-Ab) mitigate bone loss and promote bone formation to address fracture risk in postmenopausal osteoporosis. Clinically, this treatment is administered monthly for women at high risk of fragility fractures, who are often years into menopause. Preclinical studies have demonstrated that dampening of bone formation occurs with continuous dosing at supraphysiological doses. Osteoporotic bone loss occurs rapidly during early menopause, followed by longer-term changes in bone mineralization and osteocyte activity. Whether earlier administration of lower-exposure Scl-Ab can mitigate bone loss and osteocyte-driven secondary mineralisation is unknown. The objective of this study was to evaluate the effects of early intermittent low-dose Scl-Abon: (1) osteoclastogenesis and bone resorption, (2) perilacunar remodelling, (3) secondary mineralization, and (4) osteocyte mechanosensitivity. Female retired breeder Wistar rats underwent bilateral ovariectomy and received monthly low-dose Scl-Ab injections (2 mg/kg/month) from 3 to 14 weeks post-OVX, while a control group remained untreated. Early intermittent low-dose Scl-Ab treatment increased bone formation and reduced osteoclastogenesis and catabolic gene expression ((Sost, Ctsk, Mmp9) compared to untreated rats. Treatment also decreased the percentage of empty lacunae and the number of MMP14+ osteocytes, accompanied by lower perilacunar mineral density and smaller lacunar size, indicating improved osteocyte survival and reduced perilacunar remodelling. Conversely, expression of osteocyte-mediated mineralization genes (DMP1, PHEX, OPN, ALP) and mechanotransduction-related genes (Vcl, integrins 5, V, {beta}1, CX43, Axin2, IFT88, Adcy6, Pkd1, Cav1) were reduced. Together, these findings suggest that early intermittent low-dose Scl-Ab therapy promotes surface bone formation while attenuating osteocyte-mediated secondary mineralization after initial bone loss. Mini AbstractEarly intermittent low-dose sclerostin antibody treatment reduced osteoclastogenesis, bone resorption, and perilacunar remodelling, while promoting bone formation, decreasing osteocyte apoptosis, and downregulating genes associated with secondary mineralization and mechanosensitivity in ovariectomized rats. These findings suggest early intervention with Scl-Ab enhances bone formation and limits osteocyte apoptosis and subsequent secondary mineralization.

molecular biology↗

bioRxiv2021

A Patient-Specific Model of Transcatheter Valve Replacement in aBicuspid Heart Valve

Bicuspid Aortic Valves (BAVs) are a common congenital heart disease where two cusps of the aortic heart valve become fused together, this leads to two unequally sized leaflets compared to the normal trileaflet valve. Transcatheter Aortic Valves are currently used in off-label treatmet of stenosed BAVs, however, due to the abnormal valve anatomy, debate surrounds the sizing of transcatheter valves. In this study, finite element models were developed to simulate the deployment of two different valves sizes (a 25 mm and a 27 mm) of the Lotus valve into the patient-specific aortic root geometry of a clinical stenosed BAV case. These models were used to investigate and compare the eccentricity, stress and mal-apposition of the two valve sizes. The results demonstrated that the 25 mm valve was the most suitable in terms of eccentricity and stress reduction. It was also shown that the smaller 25 mm valve size did not increase the likelihood of mal-apposition. As the 25 mm valve was deemed suitable based on current sizing algorithms, on the basis of these results traditional annulus measurement and device sizing may be suitable in the case of the Lotus valve.

bioengineering↗