Antagonizing microRNA-19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice.

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.

PAIN-less identification and evaluation of small molecule inhibitors against protein tyrosine phosphatase 1B.

A highly miniaturized biochemical assay was set up to test a focused set of natural products against the enzymatic activity of protein tyrosine phosphatase 1B (PTP1B). The screen resulted in the identification of the natural product alkaloids, berberine and palmatine as well as α-tocopheryl succinate (α-TOS) as potential inhibitors of PTP1B. In a second step, several read-out and counter assays were applied to confirm the observed inhibitory activity of the identified hits and to remove false positives which target the enzymatic activity of PTP1B by a non-specific mechanism, also known as PAINS (pan-assay interference compounds). Both, berberine and palmatine were identified as false positives which interfered with the assay read-out. Using NMR spectroscopy, self-association via stacking interactions was detected for berberine in aqueous media, which may also contribute to the non-specific inhibition of PTP1B. α-TOS was confirmed as a novel reversible and competitive inhibitor of PTP1B. A concise structure-activity relationship study identified the carboxyl group and the saturated phytyl-side chain as being critical for PTP1B inhibition.