Investigators funded in part by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have identified a chemical compound that increases bone mass in mice. The compound, which blocks parathyroid hormone (PTH) signaling, offers a promising new approach for treating osteoporosis and related conditions. The study appeared in Nature Communications.
While our bones may seem static, in fact they are in constant flux. There is a continuous balancing act between cells called osteoblasts, which work to form bone, and cells known as osteoclasts, which degrade bone. A third type of cell, the osteocyte, sends signals to stimulate bone growth or loss. Osteoporosis occurs when the balance is upset and bone breakdown gains the upper hand. The condition affects roughly 10 million Americans, and brings an increased risk of bone fractures and associated health problems.
A drug derived from PTH called teriparatide is the only approved therapy for osteoporosis that boosts bone formation, but the details of how it works remain unclear. A better understanding of how the drug exerts its effects would enable researchers to design new and better options for promoting bone mass.
Henry M. Kronenberg, M.D., of the Massachusetts General Hospital, together with an international team of investigators, set out to provide some clarity by focusing on untangling the signaling pathways that PTH triggers in osteocytes. Marc Wein, M.D., Ph.D., then a postdoctoral researcher in Dr. Kronenberg’s lab and currently an independent investigator at Massachusetts General Hospital, discovered that an enzyme called SIK2 plays a key role. PTH acts through SIK2 to block the production of a protein called sclerostin, thereby boosting bone formation.
Additional experiments revealed that PTH works simultaneously through SIK2 to bring about a rise in RANKL levels. RANKL is a well-known signaling molecule that acts to erode bone by stimulating the bone-degrading osteoclasts.
SIK2’s pivotal role in PTH signaling suggested that it might be a good target for treating osteoporosis, especially if the enzyme’s effect on bone formation could be made to outweigh its effect on bone erosion. To test the idea, the investigators first screened an array of small chemical compounds for their capacity to block SIK2’s activity. They identified several closely related molecules and found that they mimicked PTH’s effect—lowering sclerostin levels and increasing RANKL production in cultured osteocytes.
Encouraged by these results, the researchers went on to test the impact of the SIK2 blockers on bones in animals. A daily dose of one blocker, YKL-05-099, to male mice produced faster bone formation and an increase in bone mass after two weeks.
However, the data also revealed a surprising result—YKL-05-099 treatment lowered bone-degrading osteoclast numbers in the mice, despite a rise in RANKL production. Additional studies are needed to understand this unexpected but desirable effect for enhancing bone mass.
"Teriparatide, the only FDA-approved drug for osteoporosis that stimulates new bone formation, has some shortcomings—it begins to lose its effectiveness after a year or so, has to be injected daily and may bring an increased risk of tumors," said Dr. Kronenberg. "Our work, by identifying small molecules that block the same pathway, lays the foundation for the development of new therapies that lack these drawbacks."
This study was supported by the NIAMS (P30-AR066261, K08-AR067285 and R03-AR059942) and the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (P01-DK011794). The Ellison Foundation also contributed support.
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SIKs control osteocyte responses to parathyroid hormone. Wein MN, Liang Y, Goransson O, Sundberg TB, Wang J, Williams EA, O'Meara MJ, Govea N, Beqo B, Nishimori S, Nagano K, Brooks DJ, Martins JS, Corbin B, Anselmo A, Sadreyev R, Wu JY, Sakamoto K, Foretz M, Xavier RJ, Baron R, Bouxsein ML, Gardella TJ, Divieti-Pajevic P, Gray NS, Kronenberg HM. Nat Commun. 2016 Oct 19;7:13176. doi: 10.1038/ncomms13176. PMID: 27759007
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