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Osteoblast adherence to bone surfaces is important for remodeling bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matrices in vitro. Furthermore, Tgif1 acts as a transcriptional repressor of p21-activated kinase 3 (Pak3), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased Pak3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1–34 (PTH 1–34) treatment in vivo in mice. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.

Breast and prostate cancer are among the most common malignancies worldwide. After treatment of the primary tumor, distant metastases often occur after a long disease-free interval. Bone is a major site for breast and prostate cancer metastasis and approximately 70% of patients with advanced disese suffer from osteolytic or osteoblastic bone metastases, a stage at which the disease is incurable. In bone, the disseminated tumor cells (DTCs) can become quiescent or “dormant”, a state where they are alive but not actively dividing. Alternatively, the cancer cells can proliferate, disturb the bone homeostasis, and form metastatic lesions. The fate of cancer cells is largely dependent on the bone microenvironment, particularly the bone forming osteoblasts and bone resorbing osteoclasts. Osteoblasts originate from mesenchymal precursors through a tightly regulated cascade. The main function of osteoblasts is to synthesize bone matrix, coordinate mineralization and maintain bone remodeling by regulating osteoclast activity and bone resorption. In metastatic bone environment, osteoblasts can create a niche within the bone where DTCs cells become dormant and induce quiescence in cancer cells keeping them in a non-proliferative state. Osteoblasts also contribute to metastatic outgrowth and actively promote tumor growth in bone. In this article, we review the recent literature on the role of osteoblasts in cancer cell dormancy and bone metastasis and describe the underlying mechanisms by which osteoblasts regulate cancer cell fate in bone. In addition, we discuss the possibility of targeting osteoblasts to treat osteolytic bone metastases.

The TAM family of receptor tyrosine kinases exerts pleiotropic functions in health and disease. Here, the authors show that TAM receptors control osteoblastic bone formation and identified MERTK as a novel target for bone anabolic therapy and mitigation of bone metastasis including its associated osteolytic bone disease

Abstract Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone‐related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl‐Ab). Here, we show that PTH and Scl‐Ab reduce the expression of microRNA‐19a and microRNA‐19b (miR‐19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR‐19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR‐19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG‐interacting factor 1 (Tgif1) as the target of miR‐19a/b in osteoblasts and essential for the increase in bone mass following miR‐19a/b inhibition. Furthermore, antagonizing miR‐19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF‐κB ligand (RANKL)‐dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

Prostate cancer bone metastasis is still one of the most fatal cancer diagnoses for men. Survival of the circulating prostate tumor cells and their adaptation strategy to survive in the bone niche is the key point to determining metastasis in early cancer stages. The promoter of SFRP2 gene, encoding a WNT signaling modulator, is hypermethylated in many cancer types including prostate cancer. Moreover, SFRP2 can positively regulate osteogenic differentiation in vitro and in vivo. Here, we showed SFRP2 overexpression in the prostate cancer cell line PC3 induces an epithelial mesenchymal transition (EMT), increases the attachment, and modifies the transcriptome towards an osteoblast-like phenotype (osteomimicry) in a collagen 1-dependent manner. Our data reflect a novel molecular mechanism concerning how metastasizing prostate cancer cells might increase their chance to survive within bone tissue.