Proteoglycan-4: A Dynamic Regulator of Parathyroid Hormone Biologic Actions.

Abstract

Intermittent parathyroid hormone (PTH) (1-34) is the only anabolic agent currently approved for the treatment of osteoporosis in the U.S. PTH (1-34) is under clinical investigations as a local bone regenerative therapy and as a potential stem cell therapy following bone marrow transplants. While PTH has known actions increasing bone mass and supporting the expansion of hematopoietic progenitor cells (HPCs), the mechanisms mediating such actions are poorly understood. Most recently it was reported that intermittent PTH protects articular cartilage in degenerating joints.

Proteoglycan 4 (Prg4), a novel PTH-responsive gene, was investigated as a potential mediator of PTH biologic actions. Prg4 protein product actions have been implicated in articular joint protection, HPC expansion, and megakaryopoiesis. Loss-of-function mutations in PRG4 result in camptodactyly-arthropathy-coxa vara-pericarditis syndrome, which is characterized by precocious joint failure and osteopenia. The overall hypothesis that proteoglycan 4 mediates PTH actions in hematopoiesis, skeletal anabolism, and degenerating joints was investigated using in vitro and in vivo strategies with Prg4 null mice.

The investigation of proteoglycan 4 effects on hematopoiesis in adult Prg4 mutant mice revealed that proteoglycan 4 is an immunomodulatory factor regulating physiologic immune cell populations and PTH actions increasing HPCs. SDF-1 was identified as a strong candidate regulator of proteoglycan 4 actions on hematopoiesis. Skeletogenesis studies demonstrated that proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass in the developing skeleton. In the mature remodeling skeleton proteoglycan 4 appears to indirectly support skeletal homeostasis and PTH anabolic actions by protecting joint function. Findings that PTH regulated gene expression similarly in bone and liver highlight the liver as a potential mediator of PTH biologic actions. The joint investigation identified increased joint SDF-1 levels as a novel candidate mechanism mediating articular cartilage degeneration in Prg4 mutant mice.

This dissertation study of the impact of proteoglycan 4 on the actions of PTH in hematopoiesis, skeletal anabolism, and degenerating joints advances our understanding of the mechanisms mediating PTH biologic actions. Moreover, this body of work further elucidates the role of proteoglycan 4 in physiologic hematopoiesis, skeletogenesis, and joint protection.