Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis

Arthritis Rheum. 2006 Jun;54(6):1736-46. doi: 10.1002/art.21897.

Abstract

Objective: The balance between destruction and homeostatic or reparative responses determines the outcome of arthritis. Increasing evidence suggests a role for signaling pathways, essential for development and growth, in the maintenance of tissue homeostasis and attempts at repair. Inappropriate activation of such pathways may also have a role in disease progression. We undertook this study to determine the effect of shifting the balance in bone morphogenetic protein (BMP) signaling in different mouse models of arthritis.

Methods: Endogenous levels of noggin, a BMP antagonist, were reduced using heterozygous noggin(+/LacZ) mice in a model of inflammation-driven destruction (methylated bovine serum albumin [mBSA]-induced monarthritis), a model of systemic autoimmune arthritis (collagen-induced arthritis [CIA]), and a model of joint ankylosis (spontaneous arthritis in DBA/1 mice). In addition, we studied BMP inactivation by adenoviral noggin overexpression in destructive arthritis. Cartilage damage and activation of BMP signaling were studied by digital image analysis using Safranin O sulfated glycosaminoglycan staining and immunohistochemistry for phosphorylated Smads (Smads 1, 5, and 8), respectively.

Results: Noggin haploinsufficiency provided protection for articular cartilage against destruction in mBSA-induced arthritis. Antagonist overexpression rendered cartilage more vulnerable in this model. Noggin gene transfer in knees affected by CIA also enhanced cartilage damage. Haploinsufficiency did not affect CIA, but noggin(+/LacZ) mice had an increased number of CD4-positive cells with normal immune responses. In noggin(+/LacZ) DBA/1 mice with spontaneous arthritis, we observed delayed progression from cartilage to bone formation.

Conclusion: Tight spatiotemporal control of BMP signaling appears to be critical in the response of joint tissues in models of arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / physiopathology*
  • Bone Morphogenetic Proteins / physiology*
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology*
  • Cartilage, Articular / pathology
  • Disease Progression
  • Gene Transfer Techniques
  • Homeostasis / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Osteogenesis / physiology
  • Serum Albumin, Bovine / pharmacology
  • Signal Transduction / physiology

Substances

  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • methylated bovine serum albumin
  • noggin protein
  • Serum Albumin, Bovine