One Protein, Two Cures: Harnessing Sclerostin’s Dual Nature to Tackle Osteoporosis, Osteoarthritis

Sclerostin plays a crucial role in bone formation but also restrains abnormal bone growth in joints, which can worsen osteoarthritis. This paradox inspired the design of two short peptides with opposite functions — one restores bone in osteoporosis, while the other protects cartilage in osteoarthritis

Fragile bones and stiff, painful joints are two of the most common causes of disability and suffering in older adults. Osteoporosis leads to fractures even after minor falls, robbing people of independence, while osteoarthritis slowly erodes cartilage and mobility, making everyday activities a challenge.

These are not rare conditions. Osteoporosis affects more than 200 million people worldwide, and osteoarthritis remains the leading cause of disability among the elderly. In India, both diseases are rising rapidly with the ageing population, compounded by high rates of diabetes, early menopause, and chronic kidney disease.

Despite their scale, current treatments for these disorders remain limited in scope and burdened by risks. Our study published recently now shows that two short peptides, designed from the same protein, sclerostin, may hold the key to safer, more effective therapies. One peptide restores bone in osteoporosis, while the other protects cartilage in osteoarthritis.

The scale of the problem

Osteoporosis is often called the “silent thief of bone” because its damage remains hidden until a fracture occurs. Hip fractures are particularly devastating, with high rates of long-term disability and even mortality. In India, osteoporosis is underdiagnosed, and osteoporotic fractures often result in a permanent loss of independence.

Osteoarthritis, in contrast, is overtly symptomatic. It causes pain, stiffness, and swelling in joints, and its progression can leave individuals unable to walk without assistance. The socioeconomic burden is immense, given the costs of pain management, physiotherapy, and joint replacement surgeries.

Existing drugs for osteoporosis provide only partial solutions. Teriparatide (a peptide drug derived from parathyroid hormone) stimulates new bone formation but fails to suppress bone breakdown. Romosozumab, a monoclonal antibody that neutralises sclerostin, manages to do both but carries cardiovascular risks and limited treatment duration. For osteoarthritis, there is no disease-modifying drug at all; management relies on symptomatic treatment until surgical intervention becomes necessary.

What is sclerostin?

Sclerostin is a protein secreted by osteocytes, the most abundant and deeply embedded cells in bone. Its main role is to regulate the Wnt signalling pathway, a critical driver of bone formation. By binding to receptors on bone-forming cells (osteoblasts), sclerostin acts as a brake, limiting the formation of new bone.

Genetic studies first revealed its importance: people with rare mutations that inactivate the sclerostin gene develop conditions such as sclerosteosis and van Buchem disease, characterised by unusually dense bones. These natural “experiments” showed that blocking sclerostin could be a powerful way to build bone, which led to the development of romosozumab, an antibody therapy.

However, sclerostin’s role is not limited to bone. In joints, it helps restrain abnormal bone growth that can worsen osteoarthritis. This paradox — harmful in one context, protective in another — makes sclerostin a classic example of a Janus-like protein. It was precisely this paradox that inspired the design of two short peptides with opposite functions: one to block sclerostin in osteoporosis, and one to mimic it in osteoarthritis.

The Janus-like insight

Sclerostin itself provided the clue for a different approach. Excess sclerostin after menopause leads to weaker bones, contributing to osteoporosis. Yet paradoxically, in joints, sclerostin protects against abnormal bone growth and preserves cartilage.

This paradox recalls the concept of Janus-like proteins, named after the Roman god with two faces. Several proteins are known to have such duality, with distinct domains exerting opposite effects. Examples include p53 and nuclear factor kappa B (NF-κB) in cell death and survival, or parathyroid hormone (PTH) and PTH-related protein (PTHrP), which contain fragments that act as both agonists and antagonists of PTH receptor.

Guided by this concept, it was hypothesised that sclerostin might also contain separate regions with opposing functions. If identified, these regions could serve as templates for short peptides that either antagonise sclerostin (to boost bone formation in osteoporosis) or mimic its inhibitory role (to prevent pathological bone formation in osteoarthritis).

Designing the peptides

Through nuclear magnetic resonance (NMR) studies and molecular modelling, sclerostin’s structure was carefully dissected. Three candidate peptides were designed, and two emerged as particularly effective:

– SC-1 (18 amino acids, derived from loop 2 of sclerostin): Functions as a sclerostin antagonist, enhancing Wnt activity to promote bone formation.
– SC-3 (14 amino acids, derived from loop 3): Acts as a sclerostin mimic, inhibiting Wnt activity to slow abnormal joint bone growth.

Short peptides offer several advantages over monoclonal antibodies. They are easier and less expensive to synthesise, reducing eventual drug costs. They also carry a lower risk of triggering immune reactions. These features make them attractive as drug candidates, especially for conditions like osteoporosis that require long-term management.

SC-1: building back bone

SC-1 was tested in animal models of postmenopausal osteoporosis and chronic kidney disease (CKD)-induced bone loss. The results were striking. SC-1 restored bone mineral density, improved trabecular architecture, and enhanced mechanical strength.

Crucially, SC-1 achieved what only romosozumab had previously managed — it both stimulated bone formation and suppressed bone resorption, rebalancing bone turnover. Unlike romosozumab, however, SC-1 showed no cardiovascular side effects and no immunogenicity. Compared with teriparatide, SC-1 produced more sustained skeletal benefits.

The effect in chronic kidney disease was especially important. Patients with chronic kidney disease often suffer from osteoporosis but are excluded from existing treatments because of safety concerns. In these models, SC-1 not only corrected bone fragility but also improved kidney parameters, addressing a therapeutic void that has persisted for decades.

The simplicity of design adds to its promise. Being a short peptide, SC-1 can be synthesised at much lower cost than complex biologics such as romosozumab. This could make it an affordable, accessible option in low- and middle-income countries where osteoporosis is a growing public health challenge.

SC-3: protecting joints

SC-3 was evaluated in animal models of osteoarthritis, where it consistently prevented disease progression. Regular injections of SC-3 preserved cartilage, reduced osteophyte formation, and normalised subchondral bone volume.

A further innovation was the delivery system. SC-3 was formulated in a shear-thinning hydrogel, which allowed for a single injection to achieve the same therapeutic effect as eight weekly doses. This addresses the challenge of patient compliance in intra-articular therapies and offers a practical advantage for long-term treatment.

At the molecular level, SC-3 shifted the balance of gene expression. It suppressed pathways that drive abnormal bone growth (including Runx2 and BMP-2) while enhancing those that support cartilage maintenance and repair (such as SOX-9 and COL2A1). The result was a joint environment more favourable for preserving mobility and cushioning.

A safer, smarter alternative

Both SC-1 and SC-3 demonstrate the strengths of peptide therapeutics. Unlike monoclonal antibodies, which fully block their targets and can lead to systemic complications, peptides provide more selective modulation. Their smaller size and simpler design make them easier to produce and less likely to provoke adverse immune reactions.

This positions SC-1 and SC-3 as potential first-in-class therapies for osteoporosis and osteoarthritis — conditions where treatment options are currently either risky, incomplete, or entirely absent.

Implications for India and beyond

The discovery has implications beyond science. India is facing an ageing population and a rising burden of lifestyle-related diseases that exacerbate osteoporosis and osteoarthritis. Yet access to advanced biologics remains limited due to cost barriers.

By developing home-grown, affordable peptide-based therapeutics, India can both address its own public health needs and contribute globally to bone and joint disease management. The approach also provides a template for exploiting Janus-like properties of proteins in other disease contexts, where distinct fragments could be harnessed to design drugs with opposing but complementary functions.

Our work exemplifies how India can transition from primarily consuming global innovations to creating new therapeutics with worldwide impact.

The road ahead

While the preclinical results are encouraging, translation to the clinic will require careful steps. Toxicology studies, regulatory approvals, and multi-phase clinical trials must confirm that the safety and efficacy observed in animal models hold true in humans.

If successful, SC-1 and SC-3 could emerge as the first dual solutions to two of the most pressing skeletal diseases — rebuilding bone in osteoporosis and protecting joints in osteoarthritis.

The journey from hypothesis to discovery illustrates how a paradox in protein biology can be turned into an opportunity for therapeutic innovation. From one protein, two cures are now within reach.