Major progress in understanding osteoclast function

Osteoclasts are large multinucleated cells that are responsible for bone degradation (resorption) in all vertebrate animals. Merry Jo Oursler, Ph.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minn., explains: "The rate at which bone is lost depends mostly on the number of osteoclasts in contact with the bone. In young adults, the amount of bone lost through osteoclast activity is replaced by new bone formation. This coupling of bone resorption to bone formation breaks down with aging. With age, increased osteoclast activity causes osteoporosis that can lead to debilitating fractures.

"Our interests are to uncover the mechanisms that regulate bone resorption, how bone resorption is coupled to formation, and how these mechanisms break down with aging. Our expectation is that resolving these questions will lead to more-effective therapies to prevent debilitating bone loss associated with aging." Current projects include:

Mechanisms of osteoclast fusion

The question relates to the role of the anti-adhesive protein PODXL in regulating osteoclast fusion and function. Dr. Oursler reports: "We have found that downregulation of PODXL expression is required for osteoclast fusion. Mice lacking PODXL in osteoclast lineage cells have a high bone mass in spite of an increase in the number of osteoclasts. Our studies have found that a low level of PODXL is required for proper osteoclast function through regulation of osteoclast cytoskeletal control of bone attachment and resorption. We are currently resolving the roles of PODXL in osteoclast differentiation and function."

Mechanisms by which osteoclasts control bone formation

Osteoclasts secrete several factors that recruit osteoblast precursors and promote their differentiation and bone formation. Dr. Oursler explains: "We have determined that osteoclasts secrete sphingosine-1-phosphate (S1P), bone morphogenetic protein 6 (BMP6) and Wnt10b. S1P recruits osteoblast precursors to the bone surface and both BMP6 and Wnt10b stimulate osteoblast differentiation and promote mineralization. We are examining how gene expression of these factors is modulated during osteoclast differentiation and how they function to promote bone formation."

Changes in osteoclast control bone formation with aging

Although numerous therapies exist to prevent osteolysis and bone loss, there is still a paucity of anabolic therapies. Dr. Oursler says: "A new and promising anabolic therapy is an antibody that neutralizes sclerostin and thereby enhances Wnt stimulation of bone formation. We have discovered that early osteoclast precursors secrete sclerostin, which inhibits Wnt effects on osteoblasts. During osteoclast differentiation, sclerostin expression is suppressed, allowing coupling of bone resorption to subsequent bone formation. Osteoclasts from aged, but not young, mice secrete sclerostin, and this could uncouple bone formation from bone resorption. We are examining the role of osteoclast sclerostin in the uncoupling that develops with aging."

Role of Wnt signaling in regulating osteoclast differentiation and functions

Data that have not been extensively explored show that anti-sclerostin therapy also decreases osteoclast numbers and reduces bone resorption. Dr. Oursler notes: "The mechanisms responsible for this anti-resorptive phenotype are unknown. Our data support that Wnts directly inhibit osteoclast formation, and we are investigating how Wnts suppress osteoclast differentiation.

"In a mouse model for targeting genes, we deleted the Wnt signaling intermediate beta-catenin in osteoclast precursors to block canonical Wnt signaling during osteoclast differentiation. MicroCT scanning revealed that bone resorption was so extensive in bones from mice lacing beta-catenin that there were holes in the cortical bone by 17 weeks of age.

"We have found that Wnts can also activate an alternate pathway not influenced by sclerostin, and the outcome of activation of this alternate pathway is to promote osteoclast differentiation and increase bone resorption. Thus, Wnt signaling can either suppress bone resorption by reducing osteoclast differentiation or promote bone resorption by stimulating differentiation, depending on which pathway is activated. We are investigating the balance of these suppressive and stimulatory effects of Wnts on osteoclast differentiation. Our expectation is that this will allow for better targeted therapies to build bone while preventing bone loss."