Mark Johnson, Ph.D.
Dr. Johnson has long-standing interests in the molecular basis of human disease and for the past dozen years has focused on the molecular genetics of osteoporosis. Osteoporosis is a disease characterized by decreased bone mass and compromised bone strength that predisposes affected individuals to an increased risk of fracture. Osteoporosis is a major health problem in this country and around the world and the economic burden in the US is currently estimated at around $20 billion and increasing as our populations continues to live longer. It is estimated that some 40% of postmenopausal women will suffer an osteoporotic fracture in their remaining lifetime and of those 25% will die within one year of suffering their fracture and another 25% will require long-term nursing home care/special assistance and will never regain a full measure of their former lifestyle.
While at the Creighton University Osteoporosis Research Center, Dr. Johnson began working with a family that has a high bone mass (HBM) trait. He and his group localized the gene for this trait to chromosome 11 (11q12-13) and in collaboration with industry partners, Genome Therapeutics (now Oscient Pharmaceuticals) and Wyeth Pharmaceuticals he identified the HBM causal mutation in the Lrp5 gene, which is a glycine to valine substitution at amino acid position 171. The structure of this protein and position of the HBM mutation are shown in Figure below.
LRP5 and its close homolog, LRP6, are coreceptors with the frizzled tansmembrane protein for Wnt. Binding of Wnt to the LRP5/frizzled co-receptors results in activation of the b–catenin or Wnt canonical signaling pathway shown in the Figure below. Wnt binding results in a serried of phosphorylation events that ultimately leads to the association of the axin protein with the cytoplasmic tail of LRP5/6, the inhibition of GSK and the release of b–catenin into the cytoplasm where it accumulates. A small portion of the b–catenin then translocates in to nucleus where it interacts with the TCF/Lef-1 family of transcription factors and regulates the transcription of key target genes.
Our research has shown that the HBM mutation in LRP5 reduces the threshold of bone for response to mechanical load and increases the robustness of the bone formation response once that threshold for response is reached. We now know that LRP5 is absolutely required for bone to be able to respond to mechanical load through its regulation of Wnt/b-catenin signaling. Research in my laboratory is focused on understanding now LRP5 and the HBM mutation function to regulate bone mass through mechanical loading of the skeleton. Recent studies have shown that b-catenin signaling is first activated in osteocytes in response to load and clearly identifies the osteocyte as the mechanosensory cell in bone. Load appears to work through Lrp5 dependent and independent activation of the b-catenin signaling and involves autocrine and paracrine signaling between osteocytes and eventually with cells on the bone surface. We are currently attempting to define the molecular pathways that orchestrate the response to load in bone. This work involves a combination of molecular biology, cell culture and transgenic and knockout mouse approaches. We believe that by understanding the role of LRP5 in regulating the bone formation response that we may be able to develop new anabolic agents that can be used to treat and possibly cure osteoporosis.