Osteoporosis is a systemic disease that results in loss of bone density and increased fracture risk, particularly in the vertebrae and the hip. This condition and associated morbidity and mortality increase with population ageing. Long noncoding (lnc) RNAs are transcripts longer than 200 nucleotides that are not translated into proteins, but play important regulatory roles in transcriptional and post-transcriptional regulation. Their contribution to disease onset and development is increasingly recognized. Herein, we present an integrative revision on the studies that implicate lncRNAs in osteoporosis and that support their potential use as therapeutic tools. Firstly, current evidence on lncRNAs involvement in cellular and molecular mechanisms linked to osteoporosis and its major complication, fragility fractures, is reviewed. We analyze evidence of their roles in osteogenesis, osteoclastogenesis, and bone fracture healing events from human and animal model studies. Secondly, the potential of lncRNAs alterations at genetic and transcriptomic level are discussed as osteoporosis risk factors and as new circulating biomarkers for diagnosis. Finally, we conclude debating the possibilities, persisting difficulties, and future prospects of using lncRNAs in the treatment of osteoporosis.

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, β2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

Osteoclasts are multinucleated cells formed through fusion of mononucleated precursors of the myeloid lineage and are the only cells that can resorb all the constituents of the bone matrix. Our goal was to investigate the role of long non-coding RNA DLEU1 and miR-16-5p in the fusion of human primary osteoclasts and their resorptive capacity. We found DLEU1 to be markedly upregulated, whereas miR-16 was significantly suppressed, during osteoclast differentiation, suggesting a potential involvement in the multinucleation process. The knockdown of DLEU1 or the overexpression of miR-16 in human primary pre-osteoclasts from male human donors (50 years or older) impaired fusion at both early and late time-points, each in distinct ways, without affecting cell viability. Time-lapse recordings confirmed the impairment of the fusion process and showed an abrogation of the phagocytic cup fusion modality, as well as a reduction of the fusion between mononucleated precursors and multinucleated osteoclasts during DLEU1 silencing. Furthermore, mass spectrometry-based quantitative proteomics revealed that the effects of DLEU1 and miR-16 on osteoclast fusion were mediated by distinct proteins and processes. Thus, both DLEU1 inhibition and/or miR-16 overexpression hinder osteoclast fusion through modulation of different mechanisms. Moreover, decreased levels of DLEU1 specifically affected the resorption speed of pit-making osteoclasts, while increased levels of miR-16 promoted bone resorption mainly through pit-formation, impairing the resorption speed of the osteoclasts making trenches and affecting their resorbed area. Taken together, these findings identify DLEU1 and miR-16 as mediators of osteoclast fusion and activity, offering potential new therapeutic targets to ameliorate bone destruction in skeletal diseases with accentuated bone deterioration.