Skeletal Research

The skeleton is a complex tissue that is able to regulate its own mass and architecture to meet two critical and competing responsibilities: one structural and the other metabolic. The structure of bone is determined largely through its ability to respond to daily loading with intelligent remodeling. When mechanical signals are suppressed (no exercise, space travel, getting old) bone structure degenerates - and bone resorption outpaces bone formation.  If skeletal degeneration is severe it will lead to catastrophic failure with fracture.  Alternatively, daily skeletal loading leads to bone formation, enhancing not only the activity of bone osteoblasts to make new bone, but also promotes the entry of mesenchymal stem cells into the osteogenic lineage.  Our cellular and molecular biological investigations are aimed at understanding mechanical and hormonal control of bone remodeling.

Our current primary focus is to understand the role of biophysical forces experienced by the skeleton during exercise, in controlling bone remodeling.   We are interested in signaling events that enhance osteoblast activity - in particular the ability of mechanical factors to activate MAPK as well as beta-catenin.  Both signals appear to have regulatory roles not only in promoting bone formation and inhibiting bone resorption, but also in preventing mesenchymal stem cell entry into the adipocyte lineage.  Other signals which appear to have important roles in promoting bone function and repressing fat function include COX2, nitric oxide, IGF-1 and vitamin D.  Eventually we hope to be able to apply this understanding to improving bone structure by using non-pharmacologic strategies.  

In the laboratory we apply both STRAIN and SHEAR to cells. Bone cells sense and respond to low levels of either type of mechanical force, causing alterations in gene expression and their functional phenotype.  Some gene responses that we study (RANKL, osterix, RUNX2, eNOS) require activation of ERK1/2 activation by strain/shear and occur many hours after mechanical activation.  Other genes respond much more quickly (COX2, cyclin D1, WISP1) and require activation of beta-catenin.  We believe that the integration of these two pathways results in the "loaded response"- i.e., a positive enhancement of bone structure.  Whether the same response controls the allocation of stem cells into bone or fat lineage is also a major investigative thrust in the lab in 5030 Burnett-Womack, UNC.

Current members of the UNC lab include:

• Natasha Case PhD
• Buer Sen MD
• Zhihui Xie MD
• Maya Styner MD (Endocrine Fellow)
• Minxu Zou MD
• James Meeker MD (Orthopaedic resident)
• Chris O'Conor, (MD-PhD candidate, UNC)
• Jacob Thomas (UNC senior)
• Retired members: Meiyun Ma PhD (2006-2008 - now a pediatric resident in Texas!)

Click here to see most of us in the lab: Rubin Lab Folks

Essential collaboration is ongoing with:

• Dr. Clinton Rubin, Musculoskeletal Research, SUNY
• Dr. Ted Gross, Orthopedics, University of Washington
• Dr. Mark Horowitz, Orthopaedics, Yale University
  

I am forever in debt to my colleagues at Emory/VAMC in Atlanta, including Dr. Xian Fan, Tamara Murphy and Jill Rahnert. See them HERE.

Recent Publications

1. Case N, Ma M, Sen B, Xie Z, Gross TS,  Rubin J   2008  Mechanical loading of bone cells activates β-catenin through GSK3β inactivation, J Biol Chem 283:29196-205

2.  Sen B, Xie Z, Case N, Ma, M, Rubin CT, Rubin J  2008  Mechanical strain prevents adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal.  epub July Endocrinology (in December issue)

3. Rubin J and Rubin CT  2008 Commentary: Functional adaptation to loading of a single bone is neuronally regulated and involves multiple bones. Journal of Bone and Mineral Research 23:1369-137

4.  Rahnert J, Fan X, Murphy TC, Case N, Grassi F, Nanes MS, Rubin J  2008 A role for nitric oxide in the mechanical regulation of RANKL in bone stromal cells.  Bone 43:48-54.

5.  Rubin J et al 2007 Caveolin-1 knockout mice have increased bone size and stiffness. J Bone Mineral Res 22:1408-18.

6. Rubin J, Murphy TC, Rahnert J, Nanes M, Greenfield E, Jo H, Fan X 2006 Mechanical inhibition of RANKL expression requires activation of H-Ras×GTPase in a lipid raft dependent manner. J Biol Chem 281(3):1412-8.

7. Rubin J, Rubin C and Jacobs C 2006 Molecular pathways of mechanical signaling in bone. Gene, 367:1-16.

8. Grassi F, Fan X, Rahnert J, Weitzmann NM, Pacifici R, Nanes MS, Rubin J 2006 Bone re/modeling is more dynamic in the eNOS(-/-) mouse. Endocrinology 147:4392-9.