Current Projects

Biomaterials Induce Regeneration of Articular Cartilage through Skeletal Interoception

Degenerative disorders of the joints and skeleton are major contributors to pain, disability, loss of mobility, and declining quality of life with advancing age. The socioeconomic burden associated with degenerative musculoskeletal disorders is substantial. Despite advances in symptom management, effective disease-modifying therapies remain limited. For patients with advanced structural disease, surgical interventions—including joint replacement and spinal fusion—may ultimately become necessary. To date, the development of effective disease-modifying therapies for degenerative joint diseases.

Degeneration of articular cartilage is the onset manifestation of osteoarthritis and spinal degeneration. We recently discovered skeletal interoception—bidirectional communication between the skeletal system and the central nervous system that may contribute to the regulation of bone, cartilage and joint homeostasis. Interoception generally refers to the process by which the nervous system senses and integrates signals originating from within the body. Interoception is also described as an internal or “sixth sense,” complementing exteroception—the sensory process through which the body perceives and interacts with the external environment (https://healthylongevity.suat-sz.edu.cn)

Specifically, we found that skeletal interoception induces anabolic synthesis of superficial membrane by tuning down sympathetic norepinephrine (NE). The superficial membrane is consumed during animal activity and renewed by the underneath chondrocytes in the superficial zone (SFZ). In contrast, increase of interoceptive signaling by elevation of local PGE2 or animal running reduces sympathetic outflow to promote the anabolic renewal of superficial membrane. Thus, physical activity induces an anabolic renewal of the superficial membrane by downregulation hypothalamic NE for optimized thickness and integrity of articular cartilage.

We have developed special biomaterials for intra-articular injection to regulate the “Sixth Sense” to repair the superficial membrane of articular cartilage for osteoarthritis. Intra-articular injections of cells, materials, or drugs for treatment of osteoarthritis, but the efficacy is limited. This is based on the assumption that the superficial membrane of articular cartilage is semipermeable. Our recent research demonstrates that that the superficial membrane of articular cartilage bears mechanical loads and is basically impermeable. The superficial membrane of articular cartilage is the interface of the brain’s sixth sense to regulate the joints is the articular cartilage membrane. We have obtained preliminary protein structure of superficial membrane, which provides guidance for us in designing new biomaterials.

Local Injection of Halofuginone as Osteoarthritis Therapy

Our goal is to innovatively create effective disease-modifying therapies to treat osteoarthritis, spine disc generation, and other major skeletal diseases. Excessive active TGF-β release caused by aberrant subchondral bone remodeling is the onset of osteoarthritis (OA) and temporomandibular arthritis (Nat Med. 2013;19(6):704-712), progression of ectopic bone formation (Nat Comm, 2018 Feb 7;9(1):551) and enthesopathy (J Clin Invest, 2018 1;128(2):846-860). Therefore, development of inhibition of TGF-β activity could be an effective therapy for many skeletal diseases.

We have developed local injection of halofuginone (HF) for OA therapy. Specifically, proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated OA animals. Halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. We also conducted a few cases of clinical trial and obtained expected results. 

Febrifugine has been used in Chinese herbal medicine for more than 2000 years. The small molecule HF, a derivative of febrifugine, has been granted orphan drug status for scleroderma and Duchenne muscular dystrophy (DMD). HF has shown therapeutic promise in clinic trials for scleroderma and chronic graft-versus-host disease and is currently being investigated in effectiveness of reversing muscle fibrosis in DMD. HF-attenuated OA progression by targeting three subchondral bone pathological features in the early OA in rodent OA. HF prevented subchondral bone changes, including reduced Th17-induced osteoclast bone resorption, reduced aberrant bone formation through inhibition of TGF-β signaling and abrogated H-type blood vessel formation. Most importantly, articular cartilage degeneration was attenuated, 

Target Market & Competition
Osteoarthritis is the leading cause of disability and is predicted to affect 67 million people in the United States by 2030. The osteoarthritis therapeutics market is projected to reach $10.1 billion by 2024 from $6.8 billion in 2019, at a compound annual growth rate of 8.1%. Based on anatomy, the osteoarthritis therapeutics market is segmented into knee, hip, hand, and small-joint. The knee osteoarthritis segment is projected to grow at the highest growth rate during the forecast period. Among adults 60 years of age or older the prevalence of symptomatic knee OA is approximately 10% in men and 13% in women.

Because no disease-modifying treatment for OA currently exists, the focus of treatments targets OA symptoms. OA is the most common reason for total hip and total knee replacement, as severe cases of OA result in artificial joint replacement.

Based on drug type, the osteoarthritis therapeutics market is segmented into 4 categories:

  • Visco supplementation agents

  • nonsteroidal anti-inflammatory drugs (NSAIDs)

  • analgesics 

  • corticosteroids

Prominent players in the osteoarthritis market include:

  • Sanofi (France)

  • Horizon Therapeutics (Ireland)

  • Johnson & Johnson (US)

  • GlaxoSmithKline Plc (UK)

  • Bayer AG (Germany)

  • Abbott (US) 

  • Pfizer (US)

  • Eli Lilly (US)

  • Anika Therapeutics (US)

  • Flexion Therapeutics (US)

However, the major players in this growing market provide no disease-modifying treatments for OA, only for symptoms in the disease.

Poenaparatide Therapy for Low Back Pain

Nearly 65 million Americans report episodes of back pain in their lifetime and, of those, 16 million experience persistent or chronic low back pain (LBP). The burden imposed by LBP on health and well-being has been highlighted by the Global Burden of Disease initiative of the World Health Organization. Of 291 conditions studied, LBP ranked first in terms of associated disability and overall health burden. LBP is non-specific and often present in the absence of any abnormality other than intervertebral disc (IVDs) degeneration. Lack a clear mechanism has been a limitation in the development of effective treatments for LBP. Commonly used pharmacologic treatments include acetaminophen, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and skeletal muscle relaxants. These treatments do not modify the pathological cause of LBP, and the symptoms tend to recur after discontinuing the medication. If unsuccessful, opioids are prescribed next, with significant side effects including addiction, constipation, and possibly opioid-induced hyperalgesia (OIH).

We found that uncoupled osteoclast bone remodeling generates porosity and sensory innervation of spine endplate (EP) for low back pain (LBP) and subchondral bone for osteoarthritis pain (Nat Comm, PMID: 31822662; J Clin Invest, PMID: 32191640). Moreover, we found that TGF-β activated by osteoclasts induces migration of mesenchymal stem cells to bone resorptive sites for bone homeostasis (Nat Med, PMID: 19584867). The recruited mesenchymal stem cells then undergo differentiation for bone formation (Nat Med, PMID: 22729283) and angiogenesis (Nat Med, PMID: 25282358). Importantly, alterations of the coupling process in bone remodeling leads to many skeletal diseases and pain as common pathogenesis (Nat Med, PMID: 26457758). Importantly, we have established aging-induced spontaneous LBP and lumbar spinal instability (LSI) surgery-induced LBP mouse models. Moreover, we have demonstrated that PTH [1-34] treatment attenuates both LBP and knee joint osteoarthritis pain in animal models by inhibition of netrin/DCC-induced sensory innervation and orchestrate different signaling pathways in the skeletal system (Sci Transl Med, PMID: 37967203; Nat Med, PMID: 19584867; J Clin Invest, PMID: 24487640; Nat Cell Biol. PMID: 20139972; Bone Res, PMID: 30038820; eLife, PMID: 33646122).

To treat LBP with short duration and a regimen of every other day injection, we have developed a novel peptide poenaparatide, stimulates cAMP production 3-fold higher in activation of PTH downstream signaling compared with Forteo/teriparatide/PTH [1-34]. The enhanced cAMP signaling of poenaparatide increases the efficacy and potency to reduce LBP with injection of 3 times per week equivalent to daily injection of teriparatide. Based on these studies, we anticipate that the human poenaparatide regimen will be short duration (3 months) of every other day injection to treat LBP.  Our preclinical data indicate poenaparatide will treat an effective therapy for LBP. Phase I Clinical Trial will be open-label, single-arm, single-center Phase I study to evaluate the usability of poenaparatide in patients with discogenic low back pain.