Medication-related osteonecrosis of the jaw (MRONJ): are antiresorptive drugs the main culprits or only accomplices? The triggering role of vitamin D deficiency

Osteonecrosis of the jaw (ONJ) is a severe clinical condition characterized mostly but not exclusively by an area of exposed bone in the mandible and/or maxilla that typically does not heal over a period of 6-8 weeks. The diagnosis is first of all clinical, but an imaging feedback such as Magnetic Resonance is essential to confirm clinical suspicions. In the last few decades, medication-related osteonecrosis of the jaw (MRONJ) has been widely discussed. From the first case reported in 2003, many case series and reviews have appeared in the scientific literature. Almost all papers concerning this topic conclude that bisphosphonates (BPs) can induce this severe clinical condition, particularly in cancer patients. Nevertheless, the exact mechanism by which amino-BPs would be responsible for ONJ is still debatable. Recent findings suggest a possible alternative explanation for BPs role in this pattern. In the present work we discuss how a condition of osteomalacia and low vitamin D levels might be determinant factors

Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management

Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively). The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis), and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes

CRISPR/Cas system: an emerging technology in stem cell research

The identification of new and even more precise technologies for modifying and manipulating the genome has been a challenge since the discovery of the DNA double helix. The ability to modify selectively specific genes provides a powerful tool for characterizing gene functions, performing gene therapy, correcting specific genetic mutations, eradicating diseases, engineering cells and organisms to achieve new and different functions and obtaining transgenic animals as models for studying specific diseases. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology has recently revolutionized genome engineering. The application of this new technology to stem cell research allows disease models to be developed to explore new therapeutic tools. The possibility of translating new systems of molecular knowledge to clinical research is particularly appealing for addressing degenerative diseases. In this review, we describe several applications of CRISPR/Cas9 to stem cells related to degenerative diseases. In addition, we address the challenges and future perspectives regarding the use of CRISPR/Cas9 as an important technology in the medical sciences

Zebrafish: a suitable tool for the study of cell signaling in bone

In recent decades, many studies using the zebrafish model organism have been performed. Zebrafish, providing genetic mutants and reporter transgenic lines, enable a great number of studies aiming at the investigation of signaling pathways involved in the osteoarticular system and at the identification of therapeutic tools for bone diseases. In this review, we will discuss studies which demonstrate that many signaling pathways are highly conserved between mammals and teleost and that genes involved in mammalian bone differentiation have orthologs in zebrafish. We will also discuss as human diseases, such as osteogenesis imperfecta, osteoarthritis, osteoporosis and Gaucher disease can be investigated in the zebrafish model

The psychophysical impact that COVID-19 has on children must not be underestimated

Italy has been one of the European countries that has been most affected by the COVID\u201019 pandemic. By 16 April 2020, 159,107 Italian residents had tested positive for COVID\u201019 and these included 1,123 children, up to nine years of age (0.7%) and 1,804 adolescents, aged between 10 and 19 years old (1.1%) (1). These data were in line with the case studies reported for the Chinese population, where the respective percentage (proportion) was 0.9% and 1.2% respectively (2). A five\u2010year\u2010old Italian child, who had been affected by many previous and unspecified pathologies, died after testing positive for COVID\u201019 infection (1). The lower vulnerability of the paediatric population to COVID\u201019 seems eviden

Control of the autophagy pathway in osteoarthritis: key regulators, therapeutic targets and therapeutic strategies

Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated to cartilage dysfunctions such as osteoarthritis (OA). Due to their location in a reduced oxygen context, both differentiating and mature chondrocytes are at risk of premature apoptosis, which can be prevented by autophagy. AutophagomiRNAs, which regulate the autophagic process, have been found differentially expressed in OA. AutophagomiRNAs, as well as other regulatory molecules, may also be useful as therapeutic targets. In this review, we describe and discuss the role of autophagy in OA focusing mainly on the control of autophagomiRNAs in OA pathogenesis and on their potential therapeutic applications

Hypophosphatasia and mesenchymal stem cells: a therapeutic promise

Hypophosphatasia (HPP) is due to mutations in ALPL gene which encodes the tissue non-specific alkaline phosphatase isozyme (TNSALP). Defective/inactive TNSALP causes an increased concentration of inorganic pyrophosphate (PPi) in bone matrix that impairs bone mineralization. The accumulation of extracellular PPi observed in HPP causes impairment in bone mineralization process and leads to a disturbance of calcium and Pi homeostasis. The pathogenesis of bone hypomineralization in HPP is relatively well understood; biomedical research aiming to treatment has been focused on the most obvious approach, i.e. enzyme replacement therapy, with unsatisfactory results. More innovative therapeutic approaches can be devised nowadays, thanks to current biotechnological innovations

Ectopic expression of the osteogenic master gene RUNX2 in melanoma

The transcription factor RUNX2 is the osteogenic master gene expressed in mesenchymal stem cells during osteogenic commitment as well as in pre-osteoblasts and early osteoblasts. However, RUNX2 is also ectopically expressed in melanoma and other cancers. Malignant melanoma (MM) is a highly metastatic skin cancer. The incidence of MM has increased considerably in the past half-century. The expression levels and mutation rates of genes such as BRAF, KIT, NRAS, PTEN, P53, TERT and MITF are higher in melanoma than in other solid malignancies. Additionally, transcription factors can affect cellular processes and induce cellular transformation since they control gene expression. Recently, several studies have identified alterations in RUNX2 expression. In particular, the regulation of KIT by RUNX2 and the increased expression of RUNX2 in melanoma specimens have been shown. Melanocytes, whose transformation results in melanoma, arise from the neural crest and therefore show "stemness" features. RUNX2 plays an important role in the re-activation of the MAPK and PI3K/AKT pathways, thus endowing melanoma cells with a high metastatic potential. In melanoma, the most frequent metastatic sites are the lung, liver, brain and lymph nodes. In addition, bone metastatic melanoma has been described. Notably, studies focusing on RUNX2 may contribute to the identification of an appropriate oncotarget in melanoma

Osteogenic differentiation in healthy and pathological conditions

The interacting molecular pathways which control bone remodeling in physiological conditions during a lifelong process are described. Then, alterations of the molecular pathways regulating osteogenesis are addressed. In the aging process, as well as in glucocorticoid-induced osteoporosis, bone loss is caused not only by an unbalanced bone resorption activity, but also by an impairment of MSCs\u2019 commitment towards the osteogenic lineage, in favour of adipogenesis. Mutations affecting the expression of key genes involved in the control of bone development occur in several heritable bone disorders. A few examples are described in order to illustrate the pathological consequences of perturbation in different steps of osteogenic commitment, osteoblast maturation, and matrix mineralization, respectively. The involvement of abnormal MSC differentiation in cancer is then discussed. Finally, a brief overview of clinical applications of MSCs in bone regeneration and repair is presented

Enhanced osteogenic differentiation in zoledronate-treated osteoporotic patients

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) in osteoporotic patients. We studied 22 postmenopausal osteoporotic patients. Densitometric, biochemical, cellular and molecular data were collected before as well as after 6 and 12 months of ZA treatment. Peripheral blood MSC-like cells were quantified by colony-forming unit fibroblastic assay; their osteogenic differentiation potential was evaluated after 3 and 7 days of induction, respectively. Circulating MSCs showed significantly increased expression levels of osteoblastic marker genes such as Runt-related transcription factor 2 (RUNX2), and Osteonectin (SPARC) during the 12 months of monitoring time. Lumbar bone mineral density (BMD) variation and SPARC gene expression correlated positively. Bone turnover marker levels were significantly lowered after ZA treatment; the effect was more pronounced for C terminal telopeptide (CTX) than for Procollagen Type 1 N-Terminal Propeptide (P1NP) and bone alkaline phosphatase (bALP). Our findings suggest a discrete anabolic activity supported by osteogenic commitment of MSCs, consequent to ZA treatment. We confirm its anabolic effects in vivo on osteogenic precursors