Bone is an exquisitely evolved connective tissue that serves structural and metabolic roles in the body. Bone fragility leading to fracture is a significant medical and economic burden facing our society. Each year, 1.5 million Americans suffer an agerelated fracture, resulting in direct-care expenditures of 18 billion dollars a year and often leading to decreased quality of life or even death.

Animals with targeted mutations in a bone matrix protein (KO) are utilized to study the protein’s roles in regulating extracellular matrix (ECM) deposition and architecture and understanding how these functions relate to bone disease and fracture etiology.

The importance of skeletal loading for the maintenance/increase of bone mass was suggested as early as 1892. In addition to increased size, mechanical loading influences bone ECM quality. Since many diseases influence the mechanical integrity of bone through altered tissue quality, mechanical stimulation may be a practical way to prevent/treat ECM deficiencies.

Mouse inbred strain-specific responses in bone have been demonstrated following mechanical stimulation and bone regeneration. No study has demonstrated that the response to a genetic deletion can exhibit inbred-strain-specific characteristics, or that phenotypic changes can be modulated with mechanical stimulation. It was hypothesized that the response to a genetic deletion (the bone matrix protein biglycan, bgn), mechanical stimulation (running) and a combination of these two variables would display inbred-strain-specific characteristics in the tibiae of C57BL6/129 (B6;​129) and C3H/He (C3H) male mice.

This dissertation establishes for the first time that an inbred strain-specific response to genetic deletion exists, further develops the roles that biglycan plays in regulating collagen and mineral in vivo and links these in vivo roles with mechanical integrity. Without addition of new bone, exercise altered the pre-existing ECM which influenced tissue quality and mechanical integrity. In B6;​129 KO, exercise-induced changes in tissue composition compensated for tissue-level mechanical deficiencies, suggesting that mechanical stimulation may be effective as a therapeutic intervention for diseases associated with deficiencies in bone quality. These studies provide new insights into inbred strain research which has important implications to the proper interpretation of investigations into the effects of genetic deficiencies and loading on the skeleton.