Projects

The Cell Biology of Bone Laboratory at Mayo Clinic has several ongoing research projects related to osteoclasts and bone formation.

Here's a look at several of these research projects.

Osteoclast Stimulation of Osteoblast Recruitment and Differentiation

We are using both in vivo and in vitro approaches to determine the molecular mechanisms by which osteoclasts recruit osteoblasts and stimulate bone formation during the reversal phase subsequent to bone resorption.

We have discovered that osteoclasts secrete bone morphogenetic protein-6, Wnt10b and the chemokine sphingosine-1-phosphate to promote bone formation. We are examining the roles of each of these coupling factors and how they're regulated during osteoclast differentiation.

Because bone formation lags behind bone resorption during aging, we are examining the impact of aging on osteoclast coupling factor production.

Researchers in the Cell Biology of Bone Lab have found that osteoclast-mediated release of bone-bound transforming growth factor-beta is a crucial stimulator of coupling in mice. We are pursuing the molecular mechanisms of this and extending our coupling observations to humans.

Current anti-resorptive therapies reduce osteoblast-mediated bone formation, most likely because of osteoclast suppression. Understanding how osteoclasts promote bone formation may lead to new therapies to suppress osteoclast resorption activity while preserving anabolic osteoclast functions.

Osteoclasts Are a Source of Wnt Proteins in the Bone Microenvironment

Wnts are a family of secreted factors that are necessary for differentiation of osteoblasts. We have published research findings showing that osteoclasts express several Wnt proteins.

In order to evaluate that role of osteoclast Wnt production in bone metabolism, we have reduced expression of Wls, an intracellular protein required for Wnt processing and secretion, in osteoclasts. This causes osteopenia by reducing bone formation and elevating osteoclast numbers.

We are evaluating the role of osteoclast Wnt production in coupling of bone resorption to subsequent bone formation.

The Role of the Anti-Adhesive Mucine PODXL in Osteoclast Formation and Activity

PODXL is a heavily glycosylated and charged membrane protein that acts to repel cells.

The Cell Biology of Bone Lab has found that PODXL membrane expression must be downregulated for osteoclast precursor fusion. In mature cells, a low level of expression is required for osteoclasts to resorb bone.

We are studying the impact of the loss of PODXL on bone metabolism in vivo, the mechanisms by which it is downregulated during osteoclast differentiation, and how it functions to promote bone resorption.

The Balance of Canonical and Noncanonical Wnt Signaling Controls Bone Metabolism and Is Altered in Aging

We have discovered that the relative expression levels of canonical and noncanonical Wnt receptors in osteoclast precursors determine whether Wnt signaling suppresses or stimulates osteoclast differentiation.

We are investigating the mechanisms of Wnt control of differentiation and how the balance is altered with aging.