Abstract
Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor-transforming growth factor β type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin+ mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.
Highlights
Osteoarthritis is the most common degenerative joint disorder in the US and a leading cause of disability [1, 2]
These results indicate that early initiation of intermittent parathyroid hormone (iPTH) slowed the deterioration and hypertrophy of subchondral bone microarchitecture in osteoarthritis
These results indicate that early initiation of iPTH attenuates aberrant subchondral bone remodeling by interfering with downstream TGF-β signaling in osteoarthritis
Summary
Osteoarthritis is the most common degenerative joint disorder in the US and a leading cause of disability [1, 2]. Chronic pain is a prominent symptom of osteoarthritis, affecting nearly 40 million people in the US [3]. Pain itself is a major risk factor for the development of functional limitation and disability in patients with osteoarthritis [4]. Treating osteoarthritis pain is challenging and represents a substantial unmet medical need. Available therapies (nonsteroidal anti-inflammatory drugs, analgesics, and steroids) do not provide sustained pain relief and can have substantial adverse effects [5, 6]. Inadequate control of chronic osteoarthritis pain is a major reason that patients seek surgical treatment
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