Hyaluronidase 1 deficiency decreases bone mineral density in mice

Mucopolysaccharidosis IX is a lysosomal storage disorder caused by a deficiency in HYAL1, an enzyme that degrades hyaluronic acid at acidic pH. This disease causes juvenile arthritis in humans and osteoarthritis in the Hyal1 knockout mouse model. Our past research revealed that HYAL1 is strikingly upregulated (~ 25x) upon differentiation of bone marrow monocytes into osteoclasts. To investigate whether HYAL1 is involved in the differentiation and/or resorption activity of osteoclasts, and in bone remodeling in general, we analyzed several bone parameters in Hyal1 -/- mice and studied the differentiation and activity of their osteoclasts and osteoblasts when differentiated in vitro. These experiments revealed that, upon aging, HYAL1 deficient mice exhibit reduced femur length and a ~ 15% decrease in bone mineral density compared to wild-type mice. We found elevated osteoclast numbers in the femurs of these mice as well as an increase of the bone resorbing activity of Hyal1 -/- osteoclasts. Moreover, we detected decreased mineralization by Hyal1 -/- osteoblasts. Taken together with the observed accumulation of hyaluronic acid in Hyal1 -/- bones, these results support the premise that the catabolism of hyaluronic acid by osteoclasts and osteoblasts is an intrinsic part of bone remodeling.