“Wnt is an appealing but mysterious cascade,” said Dr. Lories. He described a fly with Wnt signaling pathway mutation that was wingless and could not fly. “This truly is a substance that can create major events.”
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Explore This IssueFebruary 2015
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Because Wnt is extremely unlikely to travel across more than one or two cells, Wnt-related proteins have very local effects on bone and cartilage, said Dr. Lories. His research on FRZB, a protein that plays a role in skeletal morphogenesis, sparked his interest in the Wnt pathway and its potential role in bone and joint diseases. FRZB may bind and inhibit Wnt. FRZB gene polymorphisms are associated with OA in humans, especially hip OA.
FRZB-knockout mice generated in his laboratory had more cartilage damage and loss of cortical bone density compared to healthy, wild-type mice, Dr. Lories said. Mice without another Wnt-binding protein, SFRP1, showed an increase of cortical bone. These findings point to the potential importance of this signaling pathway in OA pathogenesis, he said. Overexpression of FRZB and SFRP1 may overload the body’s system and have a direct effect on bone formation.
Overactivation of beta-catenin, another molecule in the Wnt signaling cascade, is associated with OA as well, Dr. Lories said. “The surprising thing is that beta-catenin can be put into the center of cartilage. If you inhibit beta-catenin in articular chondrocytes, you also can get OA,” he said.
The Wnt signaling cascade may provide many clues to OA pathogenesis, but “this is not an easy therapeutic target,” Dr. Lories said.
Cells & Loading
Bone is constantly remodeled in the joints, coupled with bone resorption by osteoclasts and formation by osteoblasts, said Dr. Cao, a bone biologist studying the effects of bone marrow mesenchymal stem cells in OA progression.
“However, at the end of each cycle, bone remodeling will not change the architecture of bone,” said Dr. Cao. Calcium in the bone helps maintain constancy, he said.
Bone loading is an important factor in this cyclical process, illustrated by different animal families. Fish, for example, have no osteoclasts, no bone loading, and no bone remodeling. When amphibians first emerged from the sea onto dry land to walk, they developed osteoclasts. Dolphins, who may have returned to the sea from land, have no mechanical loading, but are intended to have solid bone like other mammals, so they show some bone remodeling and osteoclasts, he said.
Transforming growth factor beta 1 (TGFβ1), a peptide involved in many aspects of cell function, could play a role in bone remodeling and OA, Dr. Cao said. In TGFβ1-knockout mice, bone remodeling and bone formation are decreased, and the proteins cannot migrate mesenchymal stem cells (MSCs) to the bone site. In wild-type mice with TGFβ1, stem cell migration to bone surfaces is normal, he said.