Professor and Chair of the Department of Oral and Craniofacial Sciences and Director, UMKC Center of Excellence in the Study of Dental and Musculoskeletal Tissues (CEMT)
School of Dentistry
Dr. Johnson received his B.S. in Biochemistry from the University of Minnesota in 1976. He subsequently received his Ph.D. in Biochemistry from the University of Minnesota through the Mayo Graduate School of Medicine, Mayo Clinic, in 1980. He conducted post-doctoral training in molecular biology at Baylor College of Medicine, The Department of Cell Biology. Prior to joining the faculty at the UMKC School of Dentistry, he held faculty positions at St. Jude Children’s Research Hospital, The University of Akron and Creighton University. He joined the Department of Oral Biology in the UMKC School of Dentistry as a Professor in July 2005 where he is a member of the Bone Biology group. He became Chair of the Department (renamed Oral and Craniofacial Sciences) in 2010. He serves as a Senior Editor for the journal Bone and is a reviewer for several journals, has served on a number of various national peer review study sections and is a member of the AAAS, AADR/IADR, The American Society of Bone and Mineral Research and The American Society of Human Genetics
Dr. Johnson has long-standing interests in the molecular basis of human disease and for the past twenty-five 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 and Wyeth Pharmaceuticals he laboratory 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.
Another major area of research focus in the Johnson lab is the biochemical crosstalk between skeletal muscles and osteocytes. Our recent studies suggest that specific muscles may produce factors that condition the response of the osteocyte to load and that osteocyte derived factors alter the differentiation and contractile properties of muscle cells/fibers. This crosstalk appears to involve the Wnt/β-catenin signaling pathway in osteocytes and in muscle fibers. We have also observed important differences in this crosstalk between males and females, which has focused our recent attention of the role of sex hormone receptors in modulating this crosstalk.
Recent Publications (More articles at PubMed)
Jackson, E., Lara-Castillo, N., Akhter, M.P., Dallas, M. Scott, J.M., Ganesh, T. and Johnson, M.L.: “Osteocyte Wnt/β-catenin pathway activation upon mechanical loading is altered in ovariectomized mice” Bone Reports, https://doi.org/10.1016/j.bonr.2021.101129 Received 21 May 2021; Accepted 9 September 2021 2352-1872/© 2021
Mumtaz, H, Dallas, M, Begonia M, Lara-Castillo N, Scott J, Johnson ML, Thiagarajan G, Age-related and sex-specific effects on architectural properties and biomechanical response of the C57BL/6N mouse femur, tibia and ulna. Bone Rep. 2020 Apr 23;12:100266. doi: 10.1016/j.bonr.2020.100266. eCollection 2020 Jun. PMID: 32420415
Mumtaz, H, Lara-Castillo N, Scott J, Begonia M, Dallas, M, Johnson ML, Thiagarajan G, Age and Gender Related differences in Load-Strain response in C57Bl/6 mice. Aging (Albany NY). 2020 Dec 17;12(24):24721-24733. doi: 10.18632/aging.202350. Epub 2020 Dec 17. PMID: 33346747
Lara-Castillo N and Johnson ML: Bone-Muscle Mutual Interactions Curr Osteoporos Rep. 2020 Aug;18(4):408-421. doi: 10.1007/s11914-020-00602-6. PMID: 32519283
Kola, S., Begonia, M. T., Tiede-Lewis, L., Laughrey, L., Dallas, S., Johnson, M. L., & Thiagarajan, G. Osteocyte Lacunar Strain Determination Using Multiscale Finite Element Analysis. Bone Reports. 2020 May 19;12:100277. doi: 10.1016/j.bonr.2020.100277. eCollection 2020 Jun. PMID: 32478144, PMCID: PMC7251370
DB Maurel, T Matsumoto, J Vallejo, ML Johnson, SL Dallas, Y. Kitase, M Brotto, MJ. Wacker, MA Harris, SE Harris, LF Bonewald. Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes Bone Research 7 (article #6), 2019.
Taylor, E.A., Donnelly, E., Yao, X., Johnson, M.L., Amugongo, SK., Kimmel, D.B. and Lane, N.E.: “Sequential Treatment of Estrogen Deficient, Osteopenic Rats with Alendronate, parathyroid Hormone (1-34), or Raloxifene alters Cortical Bone Mineral and matrix Composition” Calcif Tissue Int epub ahead of print, 2019.
Williams, B.O. and Johnson, M.L.: “Wnt Signaling and Bone Cell Activity” in Principles of Bone Biology 4th Edition (John Bilezikian, T. John Martin, Thomas Clemens and Clifford J. Rosen editors) pp. 177-204, 2019.
Thiagarajan G, Begonia M, Dallas M, Lara N, Johnson M. Determination of Elastic Modulus in Mouse Bones Using a Nondestructive Microindentation Technique using Reference Point Indentation. Journal of Biomechanical Engineering 140: (7) 1-11, 2018. PMCID: PMC6056200
Stern AR, Yao X, Wang Y, Berhe A, Dallas, M., Johnson ML, Yao W, Kimmel DB and Lane NE: Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats Bone Rep 8:115-124, 2018. PMCID: PMC6020081.
Srivastava T, Dai H, Heruth DP, Alon US, Garola RE, Zhou J, Duncan RS, El-Meanawy A, McCarthy ET, Sharma R, Johnson ML, Savin VJ, Sharma M.: Mechanotransduction signaling in podocytes from fluid flow shear stress. Am J Physiol Renal Physiol 314:F22-F34, 2018. PMID: 28877882.
Mark Begonia, Mark Dallas, Mark L. Johnson, and Ganesh Thiagarajan, Comparison of Strain Measurement in the Mouse Forearm Using Subject Specific Finite Element Models, Strain Gaging, and Digital Image Correlation. Biomech Model Mechanobiol 16:1243-1253, 2017
Johnson, M.L. and Recker, R.R.: “Exploiting the WNT Signaling Pathway for Clinical Purposes” Curr Osteoporosis Rep 15:153-161, 2017. PMID: 28432596
Huang, J., Romero-Suarez, S., Lara, N., Mo, C., Kaja, S., Brotto, L., Dallas, S.L., Johnson, M.L., Jahn, K., Bonewald, L.F. and Brotto, M.: “Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway”. J, Bone Mineral Res Plus 1:86-100, 2017. PMID:29104955.
Dr. Nuria Lara-Castillo (Lab Director)